Published Research - Vitamin K and Cancer
  • Cancer accounts for 13% of all deaths worldwide.
  • Micronutrient deficiency is a risk factor for cancer
  • The Triage Theory explains how the body triages food and micronutrient intake.  When there is a deficiency, nutrients are allocated towards short-term survival, and the long term needs of the body go unmet, creating risk for disease like cancer.
  • The Recommended Daily Allowance for vitamin K is based on the blood clotting requirements, and does not reflect the needs of the vitamin K dependent proteins that have been identified throughout other tissues of the body.
  • Research shows that the many populations are deficient in vitamin K, increasing their risk of developing cancer.
  • Intake of Vitamin K has been shown to reduce the risk of cancer, and it is being explored as a treatment for some types of cancer.

I am going to write about cancer, the Triage Theory and vitamin K.  Cancer is one of the leading causes of death worldwide and in 2012 will account for over 8 million deaths.  The Triage Theory posits that the body triages micronutrients, first ensuring the survival of the organism.  After immediate survival needs have been met, the rest of the nutrition becomes distributed throughout the body.  In the case of any shortage or deficiency, the other nutritional needs of the body go unmet, creating a state of deficiency.  This chronic deficiency leads to subtle metabolic damage over time which can result in diseases of aging, like cancer (Tulchinsky, 2010).

The current recommended daily allowance (RDA) for vitamin K is based on the needs of the body to ensure blood clotting.  However, there is evidence that vitamin K has a physiologic role that goes beyond coagulation.  In recent years, other key proteins that depend on vitamin K for function have been identified throughout the tissues of the body.  Vitamin K has acquired importance in the pathology of vascular calcification and atherosclerotic diseases as well as in the modulation of bone metabolism, the risk reduction of diabetes, and cancer initiation and progression (Lamson & Plaza, 2003). 

It appears that many people have a chronic deficiency of vitamin K (Cranenburg, et al 2007).   When the intake of vitamin K is deficient, the vitamin K dependent proteins go without and lose function, and according to the Triage Theory, this sets the stage for cancer. 


Cancer

Cancer is the general term referring to a group of more than 100 diseases that can affect any part of the body.  According to the World Health Organization, cancer is a leading cause of death worldwide, accounting for 13% of all deaths, or 8.2 million in 2012 (World Health Organization, 2014).  Half of all men and one third of all women in the US will develop cancer during their lifetimes.  The most common type of cancer in the United States is prostate cancer, followed by breast cancer, lung cancer and colorectal cancer (www.cancer.gov).  It is expected that 238,590 new cases of prostate cancer will be diagnosed in the year 2013, with 29,720 deaths.  The most frequent types of cancer, worldwide, are lung cancer, followed by liver and stomach cancer. 

Origins of Cancer

Cancer arises from one single cell that starts to grow out of control.

The body is made up of trillions of living cells, and we need a constant supply of new cells.  Normal body cells grow and divide into new cells and die in an orderly way.  This is called the cell cycle. 

During the cell cycle, cells constantly talk to each other ensuring they are doing the right things.  Normal cells respond to external signals via tightly regulated pathways that either trigger or repress growth.  This is called cell signaling. 

There are also internal signals within a cell, which are equally as important.  A cell has many different receptors and messengers and they can be at fault in cancer.  A common messenger within a cell are proteins, known as kinases.  Kinases are often overactive or damaged in cancer cells as important messages are not sent or received. 

When the cell signaling is disrupted, cancer can grow.  Instead of dying in an orderly way, cancer cells continue to grow and form new, abnormal cells.  This is called tumorigenesis, and is a major hallmark of cancer (Hanahan & Weinberg, 2011).  Cancer cells can also break away from the original primary tumor and spread, sometimes forming new tumors.  This is called metastasis.  Most patients die from the progressive growth of metastases (Langley & Fidler, 2011). 

Ultimately, cells become cancer cells because of DNA damage.  DNA stands for deoxyribonucleic acid and it is the manual that tells a cell how to build new proteins, packaged in the form of genes.  DNA is in every cell and it directs all the cell’s actions.  In a normal cell, there are special proteins that ‘proofread’ the genetic code, so that DNA damage is repaired, or the cell dies.  In a cell that becomes cancerous, the damaged DNA is not repaired.  Instead of the cell dying, it begins to replicate and multiply, with the same abnormal DNA. 

Angiogenesis is the term for when a cancerous tumor develops a blood supply to help it grow.  A benign tumor is noncancerous, but it can cause problems; they can grow very large and can press on healthy organs and tissues.  Benign tumors are almost never life threatening.  Some cancers, like leukemia, rarely form tumors.  Instead, these cancer cells involve the blood and blood-forming organs and circulate through other tissues where they grow. 

No matter where a cancer may spread, it’s always named for the place it started.  For example, breast cancer that has spread to the liver is called metastatic breast cancer, not liver cancer. 

Risk Factors for Cancer

The transformation from a normal cell into a cancerous cell is a multistage process that can be triggered by a variety of risk factors including environmental and chemical toxins like radiation or cigarette smoke, or biological toxins such as viruses or bacteria, or genetic potential, and aging. 

  •  Age is the single biggest risk factor for cancer, because the longer we live, the more cancer causing faults we accumulate in our DNA.  Cancer increases dramatically with age (Ames et al, 1993b; Beckman & Ames, 1998).  
  • Another risk factor is hormones, which are chemicals released by cells, glands or organs in one part of the body that affects cells in other parts of the body.  Examples would be insulin, growth hormones, thyroid stimulating hormone, testosterone, or cortisol, etc.  Hormones are a factor in about 20% of cancers, including that of the breast, prostate, ovary, and endometrium (Henderson & Feigelson, 2000; Henderson et al. 1991; Kelsey & Bernstein, 1996).
  • Factors of lifestyle are thought to contribute to over half of all cancers.
    - Smoking contributes to a large percentage of cancer deaths (American Cancer Society, 2014; Makomaski, et al, 1999, Ries et al., 2000).  Smoke contains a wide variety of mutagens and substances that are carcinogenic.  Smoking is also a severe oxidative stress and causes inflammation in the lung (Lykkesfeldt, et al., 2000).  Tobacco is a cause of cancer of the lung, mouth, pharynx, larynx, esophagus, bladder, pancreas, stomach, kidney, cervical and myeloid leukemia (IARC Working Group, 2004). 

     - Dietary factors have been estimated to account for about one third of cancer deaths in the United States (American Cancer Society, 2000; Ames et al., 1995; Doll & Peto, 1981; Reis et al., 2000).  Low intake of fruits and vegetables is associated with increased cancer incidence in many case-control studies (Block et al., 1992).  Excessive consumption of alcoholic beverages is associated with cancers of the colon, breast, oral cavity in smokers, and liver (Willett, 2001).  Current scientific attention has focused on body weight (obesity), weight gain among adults, and inadequate physical activity as risk factors for cancer (Caan, et al, 1998; Giovannucci et al, 1995; Huang et al, 1997; Vainio & Bianchini, 2002; Willett, 2001). 
  • Chronic Inflammation involves a complex biological cascade of molecular and cellular signals and a progressive shift in the type of cells present at the site of inflammation.  The cells work to destroy the source of inflammation, however other tissues are destroyed simultaneously (Bartsch & Nair, 2006; Grivennikov, et al., 2010; Grivennikov & Karin, 2010).  The longer an inflammation persists, the higher the risk of cancer (Lin & Karin, 2007; Schetter et al., 2010; Fitzpatrick, 2001; Oshima, 1994; Weitzman & Gordon, 1990; Visconti & Grieco, 2009). 
  • Viruses.  Some viruses are linked to certain types of cancer.  One example is HPA, the human papilloma virus which causes cervical cancer.  Hepatitis B and C can cause liver cancer, t-cell leukemia virus can cause leukemia, and Epstein-Barr can cause some types of childhood cancers, carcinomas and lymphomas  (American Cancer Society, 2013).
  • The genetic code and its relationship to cancer is well established.  Our everyday surrounds are full of things that are constantly damaging the DNA in our cells.  The life sustaining chemical reactions that are the products of normal metabolism, which occur naturally within in our cells, generate harmful by products which can cause DNA damage, equivalent to the same mutagens produced by radiation.  These are known as carcinogens.  Carcinogens damage DNA, causing faults in important genes that can lead to cancer (Ames, 2001; Fenech & Ferguson, 2001; Ames & Wakimoto, 2002). 
  •  Micronutrient Deficiency.  There is overwhelming evidence that a large number of vitamins and minerals are required for normal cellular function, DNA metabolism and repair, and human health and well being (Fenech & Ferguson, 2001; Ames & Wakimoto, 2002).  Micronutrient deficiencies can cause genome damage (Ames, 2001, 2003).  The genome damage caused by micronutrient deficiency is the same order of magnitude, if not greater, than the genome damage caused by environmental toxins, like radiation.  This awareness has led to the development of the new field, nutritional genomics, which is the science studying the relationship between the human genome, nutrition, and health, and the effect of nutrients on the regulation of gene expression (Nathanson et al, 2001). 

Current RDA for vitamins and minerals are based largely on the prevention of diseases of deficiency such as scurvy in the case of vitamin C, anemia in the case of folic acid and pellagra in the case of niacin, or vitamin K in the case of blood clotting.  There is a strong and growing international awareness that it is necessary to redefine RDA for the prevention of degenerative disease, such as cancer, cardiovascular disease and Alzheimer’s disease (Fenech, 2003).  An emerging focus is vitamin K deficiency in many global populations (Cranenburg, 2007).  High-dose vitamin therapies have been effective in ameliorating approximately fifty genetic diseases.  Feeding high doses of the vitamin raises the tissue concentrations, thereby increasing the availability of the needed nutrients  (Ames, 2002).


Triage Theory

Adequate vitamins and nutrients are necessary for immediate health, and they are necessary for long-term health.  The human diet requires both macronutrients, which are the main sources of calories, as well as micronutrients, which are the essential minerals, vitamins, and other biochemicals that required for virtually all metabolic and developmental processes (Ames, 2006). 

 The Triage Theory posits that when there is a micronutrient deficiency, the functions required for short-term survival take precedence.  When a chronic shortage of nutrients exists, subtle, insidious metabolic damage occurs, with the repercussions impacting future health.

In recent years, subtle long-term health effects of even modest deficiencies of micronutrients, have been unearthed (Ames, 2006; Ames, 1998; McCann & Ames, 2007; McCann, et al, 2006; McCann & Ames, 2008; McCann & Ames, 2005).  These health effects include an increase in DNA damage and cancer, neuron decay and cognitive dysfunction, mitrochondrial decay, accelerated ageing and degenerative diseases (Ames, 2005).  Using cultured human cell lines, Ames has shown that a deficiency of vitamins C, E, B12, B6, niacin, folic acid, iron or zinc appears to mimic radiation by causing single-and double-strand DNA breaks, oxidative lesions or both.  This has serious implications as half of the US population may be deficient in at least one of these micronutrients (Ames, 2001; Ames & Wakimoto, 2002).  These common micronutrient deficiencies are likely to damage DNA by the same mechanism as radiation, but they seem to be more important by several orders of magnitude (Ames, 2001; Gold et al., 2002).

McCann and Ames (2009) illustrated the Triage Theory with an analysis of vitamin K and the functional consequences of vitamin K deficiency on health.  They evaluated the scientific evidence on 16 known vitamin K dependent proteins located in tissues throughout the body, and the functional effect on health when those proteins are genetically ‘knocked out’ in specially bred mice.  They concluded that five vitamin K dependent proteins required for coagulation also had other critical functions, and when a deficiency was created, the effect was lethal.  They also identified five less critical vitamin K dependent proteins where the animal could survive a deficiency at least through weaning.  These proteins were osteocalcin, matrix Gla protein (MGP), growth arrest specific protein 6 (Gas6), transforming growth factor bi (Tgfbi) and periostin.  For example, mice bred without Tgfbi showed retarded growth, and were prone to develop increased spontaneous cancer (Coutu et al, 2008; Zhang, et al, 2009).  McCann and Ames found that even modest micronutrient deficiencies have been associated with and may cause age-related diseases such as osteoporosis, cardiovascular disease, and cancer. 

The evidence is consistent with a triage system that prioritizes the protection of vitamin K dependent functions for short-term survival, when vitamin K1 is scarce.  This is done at the expense of functions required to maintain long term health.  It appears that the body triages the availability of vitamin K, such that the coagulation factors in the liver, necessary for survival, are preferentially allocated vitamin K first, and only when there is extra vitamin K after coagulation, is it then distributed throughout the body to the other K dependent proteins that need it for full functionality and for full health (Shearer & Newman, 2008; Cranenburg, et al, 2007; Schurgers & Vermeer, 2002). 

Vitamin K deficiency has been linked to a variety of age-associated conditions, including loss of bone mineral density (Bugel, 2008; Heiss et al, 2008; Pearson, 2007; Shea & Booth, 2008; Cashman & O’Connor, 2008; Brunetti-Pierri, et al, 2007; Shearer & Newman, 2008), arterial calcification and cardiovascular disease (Jie, et al, 1996; Berkner & Runge, 2004; Braam, et al, 2004; Schurgers et al, 2008;  Schurgers et al, 2007; Vermeer & Hamulyak, 2004; Erkkila, et al, 2005; Erkkila et al, 2007;  Erkkila & Booth, 2008; Rennenberg, et al, 2010a; Rennenberg, et al, 2010b; Tkatchenko et al, 2009), insulin resistance (Yoshida, et al., 2008; Yoshida, Booth,  et al 2008), diabetes (Hung, et al, 2010), osteoarthritis (Bugel, 2008; Neogi, et al, 2006), chronic kidney disease (Schurgers et al, 2008; Pilkey, et al, 2007; Holden & Booth, 2007; Danziger, 2008; Ishimura, et al, 2008), and inflammation (Shearer & Newman, 2008; Shea, et al, 2008).

The triage theory is unique in that it proposes that age-related disease may be prevented or the risk reduced by ensuring an adequate supply of micronutrients.  Research has shown that supplementation with vitamins improves health (Church,  et al, 2003).  A vitamin supplement could be good health insurance (Bendich et al, 1997; Oakley, 1998; Fairfield & Fletcher, 2002). 

Deficient micronutrient intake is widespread not only in poor countries but also in the US, in part because of the high consumption of calorie-rich, micronutrient-poor, unbalanced diets (Ames, 2006).  The National Health and Nutrition Examination Surveys (NHANES) indicates that the diets of many in the United States do not provide adequate intakes of all of the vitamins and minerals recommended by official bodies (Rock, 2007; CDC, 2009-2010).   

The optimum intake of each micronutrient necessary to maximize a healthy lifespan is likely higher than the current RDA (Ames, 2005; Fenech, 2003).  Additionally, the optimum amount of micronutrients varies with age, constitution, and genetic makeup, meaning that the requirements of the elderly for vitamins and metabolites are likely to be different from those of the young. 

If the Triage theory is correct, the implications for public health are enormous.  Societal concern is low because no overt pathology has been associated with these levels of deficiency.  But the triage theory suggests that insidious changes could be occurring, leading to an increased risk of diseases associated with aging (McCann & Ames, 2009). 

This triage perspective reinforces recommendations that much of the population and specifically, patients taking anti coagulant therapy such as warfarin or Coumadin may not receive sufficient vitamin K for the optimal function of key vitamin K dependent proteins that are critically important for long-term health (Braam, et al 2003; Knapen et al, 2007;  Lamson & Plaza, 2003; Mizuta et al, 2006; Nimptsch et al, 2008; McCann & Ames, 2009). 


Treatments for Cancer

The Triage Theory offers evidence that explains how nutritional deficiency leads to cancer.  The Triage Theory recommends adequate nutritional supplementation as a way to prevent disease. 

The challenge will be the research.  Randomly controlled trials for micronutrients and long-term effects are extremely difficult to do for many reasons:  decades are sometimes required in long latency diseases; there are different, and often multiple, consequences of each micronutrient deficiency; large populations are required; the trials would be expensive; and unlike pharmaceutical drugs, there is no commercial incentive to study vitamins (Heaney, et al., 2006).  So outcome studies showing vitamin K intake to be preventive for cancer do not exist.

In this section, we will review the peer-reviewed, published scientific research that directly explores how treatment and supplementation with vitamin K has impacted various types of cancer.  As there are no long-term outcome studies, most of the research will focus on vitamin K being offered as a chemotherapy agent or as an adjuvant to another chemotherapy agent, or to facilitate tissue for radiation, after cancer has already been diagnosed.

Treatments.  There is no single treatment for cancer, and the treatment chosen depends on factors such as the person’s age, history, lifestyle, and type of cancer, etc.  The underlying principle of treatment is to kill cancer cells or stop them from growing.  Apoptosis or programmed cell death is a key process regulating cancer development and progression.  Therapies that cause apoptosis of cancer cells, with limited side effects, are critical in the treatment of cancer. 

For many years, surgery was the only treatment for cancer.  Later chemotherapy was developed.  Chemotherapy is the administration of drugs that will kill cancer cells or stop them from growing.  It succeeds by damaging the proteins or the DNA of the cell, so cell division does not take place.  However, chemotherapy drugs are very toxic, typically affecting normal body tissues as well as cancer cells, and have many difficult side effects, such as nausea, hair loss, and vomiting.  Chemotherapy can provide symptom relief for some patients, but its impact on survival has been modest and it can lead to unacceptable levels of toxicity (Osada, Tomita, et al., 2008). 

Radiation therapy was developed and was widely used by the 1960s.  Radiation is a cancer treatment that uses precisely targeted high energy rays to kill cancer cells.  It does this by damaging the molecules inside the cells, such as DNA and proteins, causing the cells to die.  About 40% of cancer patients will receive radiation at some point, either to treat their cancer or to relieve symptoms.  

Hormone therapy is when hormone levels are adjusted with drugs.  Hormones are chemical messengers produced by parts of the body and carried via the bloodstream to cause changes in other cells and tissues.  As hormones are implicated in some types of cancer, the treatments aim to disrupt those messages.  One example is tamoxifen which is widely used in breast cancer treatment.  Another is androgen-ablation therapy for prostate cancer, which uses drugs to lower the amount of the male sex hormone.

Immunotherapy is when drugs are used to trigger and harness the immune system to kill cancer cells.  Normally, antibodies are produced by the immune system and attach to foreign objects in the body and label them for destruction.  Researchers are trying to make antibodies that will attach themselves only to cancer cells. 

Despite these treatments, cancer is still a leading, life-threatening pathology.  So the search continues.  There is a need for novel therapeutic strategies and a promising treatment is with vitamins. 

Chemotherapy with Vitamins.  Vitamins are relatively safe agents without side effects, when compared to the toxic anti-cancer drugs used in chemotherapy.  Vitamins play essential roles in cellular reactions and maintain human health.  There is a growing realization that a lack of micronutrients can create an environment where cancer can begin.  There is also a realization that suffusing the body in those nutrients can help the body resist and combat disease.  Research has begun on supplements and micronutrients such as vitamin K as a way to reduce the odds of getting cancer, or improve the odds of surviving cancer. 


Vitamin K


In this section we will review vitamin K, and the research exploring vitamin K as a treatment, either singularly or in conjunction with other drugs, after cancer has been diagnosed.  There is no research on vitamin K as a preventive to cancer.

Vitamin K exists in two natural forms, phylloquinone and menaquinone, along with a synthetic, manmade form called menadione.  The natural forms are fat soluble and are chemically ready to be used by the body, with no known toxicity.  The different forms of vitamin K have different co-factor activities and behave differently in processes such absorption, transport, cellular uptake, tissue distribution and turnover.  After intestinal uptake, all K-vitamins are incorporated in triglyceride-rich lipoproteins and transported to the liver (Schurgers & Vermeer, 2002).   

Menadione, is a synthetic manmade derivative of vitamin K, and is better classified as a provitamin, a dietary substance that can be converted into a vitamin via normal metabolic processes.  Synthetic vitamins, although they are designed to mimic the effects of a single, naturally occurring vitamin, cannot mimic all of the actions or the pathways that natural vitamins take in the body.  Whereas we cannot ‘overdose’ on most natural vitamins, synthetic vitamins are not expelled from the body in the same way and instead build up.  In the United States, the FDA has banned menadione supplements because of their potential toxicity in human use (Wikipedia, 2014; Olson, 1999).  Large doses of menadione have been reported to cause adverse outcomes including anemia, neonatal brain damage, liver damage, or death.  While menadione has been used to treat cancer, due to its toxicity, we will not review the research in this section, as we will focus on the natural vitamin Ks that available through diet and supplements. 

Phylloquinone, also known as vitamin K1, can be found largely in green leafy vegetables, as well as in some vegetable oils, such as canola and soybean oils.  About 90% of the total vitamin K in the western diet is formed by K1.  In the eastern diet, natto may be the primary dietary source of vitamin K (Booth, Sadowski, et al., 1995; NAS/DRI, 2001; Elder, Haytowitz, et al., 2006; Schurgers, Geleijnse, et al., 1999; McCann & Ames, 2009).  Vitamin K1 can be found stored primarily in the liver, then the heart and pancreas.   Most of vitamin K1 is retained by the liver to be used for clotting factor synthesis.  It has been estimated that about 60-70% of a single dose of phylloquinone is ultimately excreted in the bile and urine within 8 hours after intake, which accounts for the relatively low circulating levels and low tissue stores of K1 (Shearer et al., 1974). 

Menaquinone, also known as vitamin K2 (VK2), comes from meats and hard cheeses, is produced by bacteria and is absorbed almost completely (Schurgers & Vermeer, 2000).  Although 90% of our vitamin K intake consists of K1, the menaquinones contribute more or less equally to the vitamin K status in humans due to a more complete absorption.  Menaquinone remains in the body longer, for up to 96 hours (Schurgers, Teunissen, et al., 2007; Schurgers & Vermeer, 2000; Schurgers & Vermeer, 2002).  Menaquinones have different subtypes, and are referred to as MK#, with the # referring to the side chain lengths in the chemical structure of the subtype.  For example, MK4 is a menaquinone with 4 units in the side chain.  There are thirteen different menaquinones known, and MK4 and MK7 have been focused on frequently. 

In contrast to vitamin K1, menaquinones are incorporated into both triglyceride lipoproteins as well as low and high density lipoproteins (LDL) and set free in the blood stream for all tissues possessing LDL receptors (Schurgers & Vermeer, 2002).  There are many proteins in the body that depend on vitamin K to be modified and activated.  These K dependent proteins, also characterized as extra-hepatic Gla proteins, are found throughout the nervous system, the heart, lungs, stomach, kidney and cartilage systems and are both a cell growth-regulating factor and a cell signaling factor   In this way, the different transport systems for vitamins K1 and K2 form the basis for their different target tissues, with the extra-hepatic tissues including bone, vessel wall, testis, kidney pancreas and lung being supplied with the menquinone from the LDL circulating in the blood stream. 

Currently, seventeen members of the Gla protein family are known, including seven proteins involved in blood coagulation which are synthesized in the liver, as well as osteocalcin (OC) synthesized in bone, matrix Gla protein (MGP) synthesized in cartilage and vessel wall, Gas 6, Gla-rich proteins, periostin and periostin-like factor (Wang et al., 2013).  Gla-rich protein (GRP) is the newest vitamin K dependent protein identified, and is being explored as a potential new vitamin K target in cancer (Cancela et al., 2012; Viegas, et al, 2014).  With the widespread occurrence of extra-hepatic Gla proteins there is interest in learning about the distribution of extra-hepatic K vitamins and the physiological importance of these proteins (McCann & Ames, 2009). 

Current dietary recommendations for vitamin K are defined for phylloquinone intake only and are based on the needs of coagulation.  But research has increasingly highlighted the importance of menaquinones, such that the International Life Sciences Institute (ILSI) Europe has selected experts on vitamin K from academia and industry to review the need for specific dietary reference values for menaquinones (Beulens, et al 2013).  Currently, human data on the absorption of menaquinones from food sources are limited to MK4, which stays in circulation for 72-96 hours (Schurgers, et al, 2007; Schurgers & Vermeer, 2000) in contrast to phylloquinone which has a relatively short half-life (Novotny, et al, 2010).  And the data indicates higher absorption and bioavailability of MK4 than phylloquinone, which may facilitate its uptake by various target tissues. 

The Triage Theory predicts that the consequence of moderate shortages of even a single micronutrient, though insufficient to cause overt symptoms, will result in insidious damage over time, leading to the acceleration of age-associated diseases, such as cancer.  Vitamin K has been studied as one of the critically important micronutrients that many people lack.  Epidemiological studies have shown a relationship between low intake of vitamin K and an increased risk of cancer.
 

Epidemiological Studies of Vitamin K

Epidemiology is the study of how frequently diseases occur in different groups of people and why, so as to prevent illness.  Epidemiological studies of vitamin K and cancer indicate that a deficiency of vitamin K is associated with an increased risk of cancer.   Nimptsch et al, (2008) assessed the intake of phylloquinone and menaquinones 4-14, in over 11,000 men and recorded the incidence of prostate cancer over an average of 8.6 years.  No association was found for phylloquinone, a non-significant inverse association was found between menaquinones and risk of prostate cancer, and a very strong inverse association was found between menaquinones and advanced prostate cancer, particularly with the menaquinones 5-9.  They observed that the risk of prostate cancer increased as vitamin K2 intake decreased.     

Recently, this study was extended to investigate vitamin K intake and the incidence and mortality of other common cancers including lung, breast, and colorectal, as well as prostate (Nimptsch et al, 2010).  They studied 24,340 people comprising the Heidelberg participants in the EPIC study (European Prospective Investigation into Cancer).  All participants in the study were aged between 35 and 64 years, and were free of cancer at enrollment.  The research showed that the 25% of participants with the highest intakes of vitamin K2 in their diet were 28 percent less likely to have died of any of the four cancers studied, when compared with the participants with the lowest vitamin K2 intake.  In addition, among those with the lowest dietary intake of vitamin K2, almost twice as many developed prostate cancer, when compared to those with the highest intake of vitamin K2.  In the study, men with the highest dietary intake of vitamin K were taking 92 ug/day or more, and women were taking 84 ug/day or more.  They have concluded that the intake of vitamin K in food is coupled with a reduced risk of cancer (Nimptsch, et al., 2010). 

In Minnesota, researchers tested the hypothesis that dietary and supplemental intake of vitamin K was inversely associated with risk of Non Hodgkins Lymphoma (NHL) and subtypes of leukemia and lymphomas.   Non-Hodgkin lymphoma is a cancer of the immune system, and is the most common cancer of the blood in the United States.  The intake of vitamin K through diet and supplements was assessed in 603 people diagnosed with NHL and in 1007 people without NHL.  The median intake of vitamin K among controls was 63.5 ug/day and 16% used a multivitamin supplement that included vitamin K.  The results showed that higher intake of vitamin K from the diet lowered the risk of developing NHL.  Those people who had vitamin K intakes of more than 108 ug/day had a 45% lower chance of developing NHL, indicating a fairly strong protective effect from vitamin K.  This association remained even after accounting for other factors such as age, sex, education, obesity, smoking, alcohol use and intake of foods with high amounts of antioxidants (Cerhan, et al, 2010). 

A recent study assessed the association between the dietary intake of different types of vitamin K and mortality in a Mediterranean population at high risk for cardiovascular disease.  A cohort analysis was conducted on 7216 participants from the PREDIMED – Prevencion con Dieta Mediterranea study.  Participants were men and women, aged 55-80, who had various cardiovascular disease risk factors, such as smoking, obesity, diabetes, etc.  The results indicated that the dietary phylloquinone intake was inversely associated with a significantly reduced risk of cancer and all-cause mortality.  In longitudinal assessments, individuals who increased their intake of phylloquinone or menaquinone during follow-up had a lower risk of cancer, and a lower risk of mortality, when compared to individuals who decreased or did not change their intake.  For those participants who increased their intake of dietary phylloquinone during the follow up, there was a significantly decreased risk in cardiovascular mortality, cancer mortality and all cause mortality.  This study showed inverse associations between increased dietary intake of both phylloquinone and menaquinone and total cancer mortality, and this association remained for both men and women, suggesting a protective role for vitamin K intake (Juanola-Falgarona, et al 2014)


Vitamin K1 - Phylloquinone

There have been a number of studies demonstrating the anticancer effects of vitamin K1.  Phylloquinone has been found to exhibit anticancer activity in a number of cell lines (stomach, nasopharynx, breast, oral epidermoid cancer and leukemia (Wu, et al, 1993), but seems to be much less potent than VK2 and VK3 (Prasad, et al., 1981;  Akedo, et al., 1992; Hitomi, et al, 2005)

K1 and Glioma Cell lines –
While some studies have found no vitamin K1 activity on glioma growth in rats and human glioma cell lines (Oztopcu, et al, 2004), a combination of vitamin K1 with Sorafenib produced marked growth inhibition and apoptosis, making that combination a promising therapeutic option for patients with glioma (Du, et al 2012).

K1 and Liver Cancer –
Following the realization that patients with liver cancer do not process vitamin K, research began on the relationship between vitamin K and hepatocellular carcinoma.  It was observed that the vitamin K restored normal clotting to the cancerous cells and also stopped them from growing.  A phase I/II trial of K1 with liver cancer patients resulted in decreased cancer growth. (Carr, 1994).  A phase 1 study involving 40 patients with hepatocellular carcinoma, who received high doses of vitamin K1 (40 mg per day) showed decreased cancer growth.  Five patients survived longer than 1 year on the treatment.  In another study conducted by the same team, 30 patients with HCC received 40 mg of oral K1 daily, and 6 had disease stabilization (4 for greater than one year, and two had it greater than two years).  In 7 patients liver function improved and in 15 patients, their prothrombin normalized and in 7 other patients, liver function improved.  A phase II trial showed no toxicity of vitamin K at doses up to 1000 mg/day (Carr, et al, 1996). 

A phase II study of 14 hepatocellular carcinoma patients employed oral K1 (20 mg) twice daily until the disease progressed. Nine patients were evaluated for response (median age: 64 (54-80); two had previous therapy with Tamoxifen, two had surgery, and one had chemoembolization.  Four patients of the nine were reported to have stable disease, while five progressed. No toxicity was found in any of the participants. (Zaniboni, , et al 1998).

Vitamin K1 can be taken with chemotherapy to improve its effectiveness (Yoshida et al 2003).  Sorafenib is an FDA approved agent for treatment of HCC, but it is problematic.  With Sorafenib, tumor shrinkage is minor and in high doses it causes multiple human toxicities.  When Sorafenib was combined with vitamin K1 to treat HCC, cell growth was inhibited (Wei, et al, 2010; Carr, et al, 2011).

K1 and pancreatic cancer -
Pancreatic cancer typically presents at an advanced stage and therefore tends to be incurable.  Only 15-20% of patients present with operable disease and unfortunately, surgery does not lead to a cure in the majority of patients (Smeenk, et al, 2005).  Adjuvant chemotherapy is often given to patients after surgical resection (Neoptolemos, et al, 2004; Oettle, et al, 2007; Regine, et al, 2008).  However, these traditional adjuvant therapies have a number of side effects and result in minimal improvements in survival (Mancuso, et al 2006).  There is a need for non-toxic targeted agents to treat pancreatic cancer, and naturally occurring K vitamins alone and in combination with Sorafenib were studied on pancreatic cell lines,.  The combination was found to substantially reduce cancer growth (Wei, et al, 2010). 

Vitamin K1 and K2 were tested on four pancreas cancer cell lines.  Two responded to the K vitamins, with 60% of the those lines showing apoptosis or cell death (Showalter, et al, 2010).  The vitamin Ks were well tolerated.  

Phylloquinone, K1 has some effects against cancer cells in some models, but its effects are much less potent than those of MK4:  in oral tumor cell lines and leukemia cells, for instance, MK4 is ten times more effective than K1 (Okayasu,  et al, 2001; Oztopcu, et al, 2004).  Whereas in brain cancer cells MK4 inhibits cell growth while phlloquinone is totally ineffective (Sun, et al, 2000).  .

 

Vitamin K2 - Menaquinones

Vitamin K2, or menaquinones have received increasing attention in recent years for their impact on cancer.   Various reports have shown that VK2 inhibits cancer cell growth and causes apoptosis in various cancer cell lines, and in some cancers, increases survival rate.

K2 and HCC
Human hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and is one of the most deadliest  (Shibuya, et al, 2005).  Vitamin K2 has been shown to safely suppress the growth of human hepatocellular carcinoma cells (HCC).  This was first described by Carr’s group in 1995.  They showed that escalating doses of VK2 inhibited the growth of HCC cells (Wang, et al 1995).  This finding has been confirmed and elaborated on by others (Nishikawa et al 1995; Bouzahzah, et al, 1995; Otsuka et al 2004).  Several other investigators have demonstrated that vitamin K2 causes cell cycle arrest (Kuriyama, et al, 2005; Hitomi et al, 2005; Mizuta, et al., 2006; Mituta, et al, 2007; Liu, et al 2007; Yamamoto, et al, 2009; Xia, et al, 2012). 

 Others have demonstrated that vitamin K2 inhibits HCC cell growth through a potent signaling pathway that can alter key proteins and other factors in the cell (Matusumoto, et al, 2006; Ozaki, et al, 2007; Enomoto, et al, 2007; Kaneda, et al, 2008; Yamamoto et al 2009; Yao, et al, 2012; Zia, et al, 2012;  Karasawa, et al, 2012). 

  • Human trials with K2 and HCC  
    Human trials, where vitamin K2 was used as a treatment agent, have had promising outcomes though not consistently.  Habu (et al, 2004) originally studied the long term effects of VK2 on bone loss in women with cirrhosis.  43 women were randomly assigned to a treatment group or to a control group.  The treatment group of 21 women received 45 mg per day of VK2.  The 19 women in the control group did not receive VK2.  Over a 7 year time period, only 2 of the 21 women in the treatment group developed HCC.  In the control group, 9 of the 19 women developed HCC. Vitamin K2 decreased the risk of HCC by 80% for the women in the treatment group and was chemopreventive. 

The spread of liver cancer into the portal vein contributes to the high mortality rate in HCC.  A Japanese trial enlisted 121 patients with HCC undergoing conventional therapy.  Patients were given 45 mg/day orally of vitamin K2, which resulted in significant improvement in survival.  Portal vein invasion (PVI) after 12 months was two percent in the treatment group compared to 23 percent in the control group (Koike, et al, 2004).  After two years, only 23 percent of the treatment group, compared to 47 percent in the control group, were found to have invasion of cancer into the portal vein (Jancin, 2002).  Otsuka (et al., 2004) also showed that vitamin K2 inhibits the growth and invasion of HCC cells, and reduces the risk of PVI.  The results of preliminary trials are intriguing and suggest a role for vitamin K2 in the prevention of primary and secondary HCC. 

 The high recurrence rate of hepatocellular carcinoma (HCC) determines the long-term prognosis for patients with HCC.  Any therapy that decreases recurrence will improve outcomes.  Mizuta (et al 2006) tested the effects of MK4 on recurrence of HCC and survival after curative treatment.  64 patients were assigned to a control group or a treatment group.  Those in the treatment group received 45 mg of MK4 daily.  They found a significant decrease in recurrence in the MK4 treatment group, and no patients had any adverse effects.  Analysis showed that the MK4 was the only factor related to the recurrence rate and improved survival.  Chu, (et al 2010) conducted a literature review and found that vitamin K2, specifically MK4, showed significantly better recurrence free survival.

There have been ongoing efforts to develop effective chemo agents, and research has focused on combining VK2 with other anticancer agents in therapy.  Yoshiji (et al, 2005) combined VK2 and perindopril, (often used to treat high blood pressure) and found that together, they had a preventive effect on rat liver cancer by suppressing angiogenesis.  VK2 has also been combined with ACR (acyclic retinoid) and studied in human HCC cell lines, and results showed that the combination synergistically inhibited the growth of cancer cells without affecting normal cells and decreased the recurrence rate of HCC (Kanamori, et al 2007), as well as suppressed the serum levels of vascular endothelial growth factor, a protein involved in cancer spreading (Yoshiji, et al, 2009). 

Some studies have found that while Vitamin K2 prevented HCC recurrence, it did not affect overall survival rates.  Hotta (et al, 2007) found that VK2 did not prevent recurrence of HCC after curative treatment.  The incidence of HCC recurrence did not differ between the two groups, 33% and 50% in the treatment and control group, respectively, and although the cumulative overall survival rate was higher in the treatment group, it was not statistically significant.  Kakizaki (et al, 2007) found that while VK2 significantly suppressed the recurrence of HCC, there was no difference in the overall survival rates.  Yoshida (et al, 2011) randomly assigned patients to receive placebo, 45 mg/day or 90mg/day K2 in a double blind fashion.  They did not find that high doses of VK2 prevented disease occurrence or death.  

  • Experimental Literature Reviews
    In recent years, there a have been systematic reviews of the published research on VK2 as a cancer preventive agent.  One meta analysis failed to confirm the benefit of VK2 in reducing the recurrence and increasing the survival in patients with HCC (Riaz, et al, 2012).  A second literature review found that treatment with MK4 was associated with a significant reduction in the two and three year tumor recurrence rates and was associated with a significant improvement in the 1, 2, and 3, year overall survival for HCC patients (Zhong, et al, 2013).


K2 and prostate cancer
Prostate cancer is the most common solid malignancy in men.  In the USA it is estimated that 241,740 new cases and 28,170 deaths will occur in 2012 (Siegel, et al, 2012).  A major focus in prostate cancer research is the discovery of better chemotherapeutic agents.  Previously, Nimptsch showed an inverse relationship between dietary intake of VK2 and risk of prostate cancer (Nimptsch et al 2008; Nimptsch, et al, 2009) in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC), suggesting that the intake of vitamin K2 may be beneficial in preventing the progression of prostate cancer.  People with low menaquinone intake in their diet had a higher risk of developing prostate cancer.  Serum undercarboxylated osteoalcin (ucOC), a biomarker of vitamin K status, was analyzed and a significant association with advanced stage prostate cancer was confirmed, strengthening the findings for dietary menaquinone intake.  It appears that vitamin K status may play a role in the etiology and progression of prostate cancer. 

Samykutty (et al 2013) conducted the first comprehensive study of vitamin VK2 as a treatment for prostate cancer.  The results of their study show that VK2 is able to suppress both androgen-dependent and androgen-independent prostate cancer cell lines via apoptosis.  Tumor growth was substantially reduced following treatment with VK2 in mice.  Additionally inflammatory genes were significantly down regulated.  This is the first comprehensive study which demonstrates the therapeutic potential of VK2 against both forms of prostate cancer.    


K2 and leukemia

Leukemia is a progressive cancer that starts in bone marrow and other blood forming organs and cause large numbers of abnormal blood cells to be produced.  Many types of leukemia exist.   Leukemia usually starts in the white blood cells and spreads to the spleen, liver, lymph nodes and other areas of the body.  White blood cells are potent infection fighters and having abnormal white blood cells can cause destruction of tissues, often resulting in death.  In 2010, there were an estimated 287,963 people living with leukemia in the United States. 

Research has demonstrated that vitamin K2, induces apoptosis in leukemia cells in vitro, and that MK4 specifically could be used in the treatment of leukemias (Yaguchi, et al, 1997).  Later research demonstrated that the VK2 specifically targeted leukemia cancer cells and didn’t damage other tissue (Yaguchi, et al, 1998; Miyazawa, et al, 2004; Yokoyama, et al, 2005; Yokoyama, et al, 2008).  This same group demonstrated that within 72 hours after exposure to MK4, growth inhibition was evident in leukemia cancer cells (Miyazawa, et al 2001). 


Differentiation therapy assumes that cancer cells are normal cells gone awry, and that they can be compelled back on a path of normal maturation.  Differentiation therapy restrains cancer growth and allows more conventional therapies to eradicate malignant leukemia cells (Nowak, et al, 2009).  In Myelodysplastic Syndrome (MDS), which is often referred to as pre-leukemia, the bone marrow begins churning out immature white blood cells (Cazzola & Malcovati, 2010).  But unlike leukemia, MDS cells can be induced to develop into mature normal blood cells (Albitar, et al 2002; Cazzola & Malcovati, 2010).  Treating MDS with Vitamin K2 does induces differentiation and potently induces apoptosis (programmed cell death) of the leukemic cells, with the effect much more prominent on blast cells than on mature white cells (Sakai et al 1994; Yaguchi, et al, 1998, Nishimaki, et al, 1999).  It’s also been shown that VK2 also induces MDS cells to differentiate into healthy white blood cells, even when full blown leukemia has developed (Sakai, et al, 1994; Miyazawa, et al, 2001).


Differentiation was also accomplished by combining vitamin K2 with vitamin D3.  The combination enhanced differentiation in a lab study of leukemia cells (Iguchi, et al, 2005).  In a clinical study, the addition of vitamin D3 to vitamin K2 more than doubled the response rate of MDS patients from 13% to 30%.  Those are big numbers for conditions traditionally difficult to treat with standard chemotherapy (Akiyama, et al. 2010).  

Vitamin K2 has been found to work in synergy with ACR (acyclic retinoid) in treating leukemia.  When combined, they inhibited the proliferation of leukemia cells by inhibiting cell growth and inducing apoptosis  (Kitigawa, et al, 2011). 

  • Human Studies
    In one of the earliest reports, a 65 year old man with MDS, who had progressed to acute leukemia was treated orally with 90 mg/day of MK4.  Within six weeks, he had experienced a significant decrease in cancer cell count and an increase in healthy platelet count.  At ten months, the dosage was reduced to 45 mg/day.  He had no side effects and continued good performance (Yaguchi, et al, 1997; Yaguchi, et al, 1999).  Another case study involved a 72 year old woman diagnosed with acute leukemia who was in remission.  When the leukemia returned eight months later, she was given 20 mg/day of VK2 (MK4) along with her original treatment protocol and after two months was cancer free.  A bone marrow analysis confirmed the complete remission of her cancer (Fujita, et al, 1998).  And in another case, an 80 year old woman with MDS and persistent anemia, received an oral dose of 45 mg/day of vitamin K2.  After fourteen months of treatment, her red blood count rose and she no longer needed blood transfusions (Takami, et al, 1999).  Similar benefits were found in a small group of MDS patients with refractory anemia, a type of MDS, in 2002 (Abe, et al, 2002)


The encouraging results from VK2 therapy have led to a multi-center pilot study in Japan of MDS and post MDS treatment with MK4.  A survey was done of 11 independent institutes conducting individual pilot studies using VK2 as a treatment.  The results showed no adverse effect for VK2.  In the institutes, 47 patients received treatment with MK4 with dosages ranging from 10 mg/day up to135 mg/day orally (83% received an oral dose of 45 mg/day).  Improvements began within 1 to 3 months.  They concluded that MK4 was a successful treatment in reducing cancer cell numbers in 71.4% of the patients.  The data was strongly encouraging for elderly patients who couldn’t tolerate intensive chemotherapy or stem cell transplantation and indicates that VK2 was chemopreventive against leukemia (Miyazawa, et al 2000). 


K2 and colon cancer
Colon cancer is when cancer starts in the colon or rectum, and is referred to as colorectal cancer or colon cancer for short.  Colon cancer affects men and women of all racial and ethnic groups and is most often found in people over 50 years.  It is the second leading cause of cancer death in men and women in the United States.  It is typically treated with surgery, however in Stage 3 or 4, some chemotherapies are applied. 

Research has demonstrated that vitamin K2 has antitumor effects on gastric cancer and on colorectal cancer (Tokita, et al., 2006; Ogawa, et al, 2007; Kawakita, et al, 2009), and on cancer of the bile ducts (Enomoto, et al, 2007).  Newly synthesized derivates of vitamin K2 were shown to have anti-tumor effects on various cancers, and also on colon cancer cells resistant to radiation (Amalia, et al 2010). 


K2 and lung cancer

Lung cancers are notoriously aggressive and difficult to treat.  In several different types of lung cancer, including small cell, squamous cell and adenocarcinomas, vitamin K induces apoptosis through activation of a suicide protein.  Treatment with VK2 resulted in cell growth suppression in all cell lines tested (Yoshida, et al., 2003). 

Clinical trials of newer chemotherapy agents have been disappointing but when vitamin K was added to one new drug, imatinib mesylate, a growth inhibitor of small cell lung cancer (SCLC), it rapidly suppressed growth in all lung cancer cell lines tested (Yokoyama et al, 2005).  Since VK2 is a safe medicine without prominent adverse effects, patients with SCLC may derive therapeutic benefits from this treatment combination.


K2 and ovarian cancer
Ovarian cancer is the fifth most common cancer among women and approximately 200,000 women are diagnosed with ovarian cancer ever year in the world (Parkin et al, 2005).  The primary treatment of ovarian cancer is surgery, followed by chemotherapy, and sometimes radiation.  Ovarian cancer can become resistant to standard chemotherapy (Giaccone 2000; Hennessy et al., 2009) and as a result, most ovarian cancers relapse.  However, as the survival rate for relapsed patients is low, there is an urgent need for more effective chemotherapeutic treatments.

Vitamin K2 has been explored as a promising chemotherapy agent (Nakaya et al, 2012).  The effect of vitamin K2 (MK4), on various lines of human ovarian cancer cells was studied and was found to selectively induce apoptosis in ovarian cancer cells, as well as in pancreatic cancer cells (Shibayama-Imazu et al, 2003, 2006, 2008 a and b). 


K2 and bone cancer
In the United States, more than 3000 people will be diagnosed with bone cancer, and almost half of them will die from the disease.  Vitamin K2 plays an important role in bone metabolism (Tabb et al 2003).  Studies have shown that vitamin K2 is an effective anticancer agent for osteosarcoma cell lines.  A human osteosarcoma and a mouse osteoblastic cell line were cultured for 3 days in medium containing various concentrations of MK4.  The human osteosarcoma cell line were suppressed by vitamin K in a dose dependent manner, 56% more than the control group, and 84% more in the mouse osteoblastic cell line.  Their results showed that vitamin K2 modulates proliferation and function of osteoblastic cells (Akedo, et al, 1992).

Myeloma is cancer of the bone marrow.  Myeloma cells and lymphoma cells were sensitive to VK2, which caused growth inhibition, and apoptosis.  It has clinical advantages as it can be taken orally and has few side effects (Tsujioka, et al 2006). 


K2 and glioma
Glial cells support the nerve cells of the brain.  A tumor of glial cells is a glioma.  Gliomas can be difficult to treat as it can be a challenge to get chemotherapy drugs past the blood-brain barrier.  Vitamin K gets past that barrier and actually accumulates in the brain.  Research has shown that VK2 induced growth inhibition via cell cycle arrest and apoptosis in a dose dependent manner for glioma cells in both rat and human cell types (Sun, Yoshii et al 1999)


K2 and breast Cancer

Breast cancer is the second most common type of cancer in the United States, with approximately 232,340 new cases diagnosed in 2013.  In an early study, the antitumor activities of vitamin K1, K2, and K3 were compared against a panel of human cancer cell lines, and vitamin K2 was less potent than vitamin K3  (Wu, et al 1993).  In a study of three cancer cell lines that were resistant to radiation, vitamin K2 restored sensitivity to radiation treatment and also inhibited the growth of cancer cells in breast cancer lines, as well as in lung and colon cancers (Amalia, 2010). 


K2 and pancreatic cancer
Available medical therapies against pancreatic cancer are largely ineffective and have many side effects.  Vitamin K1 and vitamin K2 were tested on four pancreas cancer cell lines.  In those cell lines, the naturally occurring, non-toxic K vitamins inhibited the survival of some pancreatic cancer cell lines by inducing apoptosis or cell death (Shibayama-Imazu et al, 2003). When vitamin K2 was combined with Sorafenib, the growth of pancreas cancer cell lines were inhibited, and lower doses were still effective (Wei, et al, 2010).  Treatment with vitamin K could benefit patients either as a single agent or in combination with chemotherapy and would help prevention recurrence of pancreatic cancer, after surgery (Showalter, et al, 2010). 


K2 and Stomach Cancer
Vitamin K2, specifically MK4, was used on four kinds of gastric cancer cell lines.  MK4 produces few serious side effects, and is safe for long term intake.  All four cell lines showed cell growth inhibition and cell cycle arrest of the cancer.  Apoptosis was induced in one of the lines, but not in the other three (Tokita et al, 2006).  It was considered that adding MK4 to other chemotherapies might allow for the side effects to be reduced by lowering the dosages of the anticancer drugs.

 

Conclusion


Vitamin K is important for your health, now and in the future. 

There is overwhelming evidence that a large number of vitamins and minerals are required for human health and well being.  The human diet requires both macronutrients and micronutrients.  Micronutrient deficiency has been linked to long term health effects such as cancer.   The Recommended Daily Allowance for vitamin K is based on outdated information and does not reflect the requirements for the menaquinones, or the requirements of the body after the coagulation needs are met.  Hence, many people are deficient in their intake of vitamin K, and this deficiency is a global health problem.

The Triage Theory explains the body’s triaging of nutrition for short term survival, which occurs at the expense of long term disease risk, such as cancer.  This may be why the single biggest risk factor for cancer is age.  The Triage Theory suggests that vitamin K is one of those critically important nutrients necessary for long term health.  Low intake of vitamin K is associated with many diseases of aging, including cancer.  Epidemiological studies confirm this and show that high intake of vitamin K is associated with lowered risk of some types of cancer. 

Research is just beginning to discover and understand the different types of vitamin K and their relationship to the health of your body.  As more is known about vitamin K1, phylloquinone, and the different menaquinones functioning in the body, research has shifted to exploring their relationship with cancer.  These early studies of vitamin K indicate it is associated with a reduction in the risk of cancer, it may be preventive to some types of cancer and that it inhibits and suppresses many types of cancer cell lines in the lab.  And, as vitamin K is safe and non-toxic at all known dosages, unlike most chemotherapy drugs, treatment with vitamin K individually or in combination with other treatments has been effective and well tolerated by patients. 

As cancer is a leading cause of death worldwide, it is very appealing to think that increasing your intake of vitamin K, either in diet and/or by a supplement, could be a simple remedy to both cancer prevention in the long-term, and perhaps as a cancer treatment.   Increasing your intake of vitamin K could be a very simple, inexpensive, and effective health insurance. 

 

 

1970s

Kerr JF.  History of the events leading to the formulation of the apoptosis concept.  Toxicology, 2002 Dec 27;181-182:471-4.


Shearer MJ, McBurney A, Barkhan P.  Studies on the absorption and metabolism of phylloquinone (vitamin K1) in man.  Vitam Horm.  1974;32:513-42.



1980s

Doll R, Peto R.  Mortality in relation to smoking:  20 years’ observations on male British doctors.  BMJ.  1976;2:1525-36.


Prasad KN, Edwards-Prasad J, Sakamoto A.  Vitamin K3 (menadione) inhibits the growth of mammalian tumor cells in culture.  Life Sciences.  1981 Sep 28;29(13):1387-92.

The effects of vitamin K, K1 and K3, on the morphology and the growth of mouse neuroblastoma (adrenal cancer), mouse melanoma and rat glioma cells in culture were studied.  Vitamin K3 inhibited the growth of all three cell types, by cell death and by partial or complete inhibition of cell division.   Neuroblastoma cells were more sensitive to vitamin K3 than were melanoma or glioma cells.  The fact that concentrations of vitamin K3 inhibit the growth of tumor cells in culture suggests that this vitamin may be a potentially useful anticancer agent. 


Waxman S, Bruckner H.  The enhancement of 5-fluorouracil anti-metabolic activity by leucovorin, menadione and alpha-tocopherol.  Eur J Cancer Clin Oncol.  1982 Jul;18(7):685-92.


Chlebowski RT, Dietrich M, Akman S, Block JB.  Vitamin K3 inhibition of malignant murine cell growth and human tumor colony formation.  Cancer Treat Rep.  1985 May;69(5):527-32.

The effects of vitamin K3, menadione, vitamin K1, phylloquinone and warfarin on murine leukemia cell growth was studied.  The combined use of vitamin K and warfarin enhanced cytotoxicity and resulted in nearly complete inhibition of growth.  They evaluated tumor types including breast, ovary, colon, stomach, kidney, lung, melanoma, bladder and liver. 


Akman SA, Carr BI, Leong L, Marolin K, Odujinrin O, Doroshow J.  Phase 1 trial of menadiol sodium diphosphate (SYNKAYVITE) in advanced cancer.  Proc Am Soc Clin Oncol.  1988;7(76):290-95. 


Ni R, Nishikawa Y, Carr BL. Cell growth inhibition by a novel vitamin K is associated with induction of protein tyrosine phosphorylation.  Biol Chem.  1988;273:9906-11.


Conly J, Suttie J, Reid E, Loftson J, Ramotar K, Louie T.  Dietary deficiency of phylloquinone and reduced serum levels in febrile neutropenic cancer patients.  Am J Clin Nutr.  1989 July;50(1):109-113.

34 cancer patients with fevers requiring antibiotic therapy, were shown to have deficient phylloquinone intakes.  The data suggest that patients with a profound deficiency of oral vitamin K intake may face greater deficiencies due to the antibiotics which would suppress menaquinone producing intestinal microflora.



1990s

Fraga CG, Motchnik PA, Shigenaga MK, Helbock JH, Jacob RA, Ames BN.  Ascorbic acid protects against endogenous oxidative DNA damage in human sperm.  Proc Natl Acad Sci USA.  1991 Dec 15;88(24):11003-6.


Henderson BE, Ross RK, Pike MC.  Toward the primary prevention of cancer.  Science.  1991 Nov 22;254(5035):1131-8.


Nutter LM, Cheng AL, Hung HL, Hsieh RK, Ngo EO, Liu TW.  Menadione:  spectrum of anticancer activity and effects on nucleotide metabolism in human neoplastic cell lines.  Biochem Pharmacol.  1991 May 1;41(9):1283-92.

The spectrum of menadione cytotoxicity was examined in a panel of human cancer cell lines.  They found that menadione was equally potent against multidrug-resistant and parental leukemia cell lines, including cervical cancer cell line.  The interactions of fifteen commonly used anticancer drugs combined with menadione were examined in vitro and the majority were found to be additive.  Collectively, these in vitro results demonstrated that menadione possesses a broad spectrum of anticancer activity.


Weitzman SA, Gordon LI.  Inflammation and cancer:  a role of phagocyte-generated oxidants in carcinogenesis.  Blood.  1990 Aug 15;76(4):655-63.


Akedo Y, Hosoi T, Inoue S, Ikegami A, Mizuno Y, Kaneki M, et al.  Vitamin K2 modulates proliferation and function of osteoblastic cells in vitro.  Biochem Biophys Res Commun.  1992 Sep 16;187(2):814-20.

A human osteosarcoma (bone cancer) and a mouse osteoblastic cell line were cultured for 3 days in medium containing various concentrations of MK4.  The human osteosarcoma cell line were suppressed by vitamin K in a dose dependent manner, 56% more than the control group, and 84% more in the mouse osteoblastic cell line.  Their results showed that vitamin K2 modulates proliferation and function of osteoblastic cells.

Block G, Patterson B, Subar A.  Fruit, vegetables, and cancer prevention:  A review of the empidemiological evidence.  Nutri and Cancer.  1992:18(1):1-29.


Ames BN, Shigenaga MK, Hagen TM.  Oxidants, antioxidants, and the degenerative diseases of aging.  Proc Natl Acad Sci.  1993 Sep; 90:7915-22.

Metabolism, like other aspects of life, involves tradeoffs.  Oxidant by-products of normal metabolism cause extensive damage to DNA, protein, and lipid.  The authors argue that this damage (the same as that produced by radiation) is a major contributor to aging and to degenerative diseases of aging such as cancer, cardiovascular disease, immune system decline, brain dysfunction, and cataracts.


Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, et al.  Nutrition intervention trials in Linxian, China:  supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population.  J Natl Cancer Inst.  1993 Sep 15;85(18):1483-92.

The researchers sought to determine if dietary supplementation with specific vitamins and minerals can lower mortality from or incidence of cancer in Linxian. China, which has one of the world’s highest rates of esophageal/gastric cardia cancer and a low intake of micronutrients.  Those who received vitamin supplements had a significantly lower mortality rate from cancer, with the reduced risk beginning to arise about 1-2 years after the start of supplementation.


Hunter DJ, Willett WC.  Diet, body size, and breast cancer.  Epidemiol Rev.  1993;15(1):110-32.


Wu FY, Liao WC, Chang HM.  Comparison of antitumor activity of vitamins K1, K3 and K3 on human tumor cells by two (MTT and SRB) cell viability assays.  Life Sci.  1993;52(22):1797-804.

In this study they compared the antitumor activities of vitamin K1, K2 and K3 against a panel of human cancer cell hepatoma (HCC) lines.  Vitamin K3 had a much greater potency of antitumor activity compared to K2 and K1 from 60-300 fold. These results support the preference for the use of VK3 in cancer therapy.


Ames BN, Shigenaga MK, Hagen TM.  Oxidants, antioxidants, and the degenerative diseases of aging.  In:  Packer L, Cadenas E, editors.  Biological Oxidants and Antioxidants.  Stuttgart, Germany:Hippokrates Verlag;1994. P 193-212.

Metabolism, like other aspects of life, involves tradeoffs.  Oxidant by-products of normal metabolism cause extensive damage to DNA, protein and lipids.  They argue that this damage is a major contributor to aging and to degenerative diseases of aging, such as cancer, cardiovascular disease, immune-system decline, brain dysfunction, and cataracts.  Antioxidant defenses against this damage include ascorbate, tocopherol, and carotenoids.  Dietary fruits and vegetables are the principal source of ascorbate and carotenoids and are one source of tocopherol.  Low dietary intake of fruits and vegetables doubles the risk of most types of cancer as compared to high intake.


Carr BI.  A phase 1/phase 11 study of high dose vitamin K (VK) to patients with advanced inoperable hepatocellular carcinoma (HCC): interim analysis.  Hepatology.  1994;20:278A.

In this study treating patients with liver cancer, high doses of vitamin K up to 1000 mg/day were administered.  There was no toxicity or difficulty experienced by the patients with that dose, and it inhibited the growth of the cancer.


Carr BL, Wang Z, Wang M, Finn F.  Prothrombin and the vitamin K cycle:  a novel endogenous growth inhibitory pathway.  Hepataology.  1994;20:272a.


Holick MF.  McCollum Aware Lecture, 1994:vitamin D-new horizons for the 21st century. Am J Clin Nutr.  1994;60:619-630.

Vitamin D is absolutely essential for the maintenance of a healthy skeleton throughout our lives.  There is mounting evidence that vitamin D insufficiency and vitamin D deficiency in elderly people is a silent epidemic that results in bone loss and fractures.  It is casual exposure to sunlight that provides most humans with their vitamin D requirement.  Seasonal changes, time of day, latitude, aging, sunscreen use, and melatonin pigmentation can substantially influence the cutaneous production of vitamin D.  There is mounting evidence that in the absence of exposure to sunlight, the vitamin D requirement is at least 600 ius/day.  Vitamin D and its analogs have been developed as an effective new therapy for the treatment of skin psoriasis.


Oshima A.  A critical review of cancer screening programs in Japan.  Int J Technol Asses Health Care.  1994 Summer;10(3):346-58.


Sakai I, Hashimoto S, Yoda M, Hida T, Ohsawa S, Nakajo S, et al.  Novel role of vitamin K2:  a potent inducer of differentiation of various human myeloid leukemia cell lines.  Biochem Biophys Res Commun.  1994;205:1305-1310.

 When leukemia cells were cultured in the presence of K2, it induced cellular differentiation.  None of these effects were observed with vitamin K1.  The results suggest that vitamin K2 may be safely and effectively used in differentiation therapy in combination with other inducers. 


Ames  BN, Gold LS, Willett WC.  The causes and prevention of cancer.  Proc Natl Acad Sci USA.  1995 Jun 6;92(12):5258-65
.

Many of the known causes of cancer are avoidable, meaning it is possible to reduce the rate of many types of cancer.  The plausible contribution of diet ranges up to 70%, likely in the range of 20%-40%.  Data emphasizes the inadequate consumption of protective factors such as vitamins and other nutrients.


Booth SL, Sadowski JA, Weihrauch JL, Ferland G.  Vitamin K1 (phylloquinone) content of foods:  a provisional table.  J Food Comp Annal.  1993;6:109-120.


Bouzahzah B, Nishikawa Y, Simon D, Carr BI.  Growth control and gene expression in a new hepatocellular carcinoma cell line, Hep40: inhibitory actions of vitamin K.  J Cell Physiol.  1995 Dec;165(3):459-67.


De Laurenzi V, Melino G, Savini I, Annicchiarico-Petruzelli M, Finazzi-Agro A & Avigliano L.  Cell death by oxidative stress and ascorbic acid regernation in human neuroectodermal cell lines.  Eur J Cancer.  1995;31:463-466.


Giovannucci  E, Rimm EB, Liu Y, Stampfer MJ, Willett WC.  A prospective study of tomatoe products, lycopene, and prostate cancer risk.  J Natl Cancer Inst.  1995;91:317-331.


Nishikawa Y, Carr BI, Wang M, Kar S, Finn F, Dowd P, et al.  Growth inhibition of hepatoma cells induced by vitamin K and its analogs.  J Biol Chem.  1995 Nov 24;270(47):28304-10. 

They investigated the mechanisms of how vitamin K inhibits cell growth.  They found that vitamin K caused growth inhibition of liver cancer cells and also caused apoptotic cell death, which could be induced at low concentrations, whereas necrotic cell death occurred at high concentrations. 


Taylor PR, Wang GQ, Dawsey SM, Guo W, Mark SD, et al.,  Effect of nutrition intervention on intermediate endpoints in esophageal and gastric carcinogenesis.  Am J Clin Nutr.  1995 Dec;62(6 Suppl):1420S-1423S.

In Linxian, China the esophageal and stomach cancer mortality rates are among the highest in the world and suspicion exists that it is due to chronic deficiencies of multiple nutrients.  In a randomized, double-blind and placebo-controlled study, multivitamin and multimineral supplements were given.  The results suggested that vitamin supplements may decrease the proliferation of the cancer.  Benefit was suggested but the results were generally statistically nonsignificant.


Wang Z, Wang M, Finn F, Carr BI.  The growth inhibitory effects of vitamins K and their actions on gene expression.   Heptaology.  1995;22:876-82. 

A characteristic defect occurs in rat and human hepatocellular carcinoma (HCC) resulting in a loss of function of the vitamin K-dependent enzyme des-gamma- carboxylase (DCP) in the tumor but not in the liver.  This leads to the secretion of elevated levels of uncarboxylated prothrombin, which is used as a marker of HCC.  They investigated whether adding vitamins K1 or K2 or K3 could influence the secretion of immature prothrombin, which all three did.  Vitamins K2 and K3 were also found to inhibit the growth of the HCC cell line, in a nontoxic and reversible manner.  The vitamins K were also found to influence the expression of genes.

 

Carr BI, Wang Z, Virji MA Piper M.  Vitamin K (VK) inhibits hepatoma cell growth in vitro and in patients (Meeting abstract).  Proc AACR. 1996;37:A1485.

Thirty patients with HCC received 40 mg daily of k1.  Seven patients had a partial response and six patients had disease stabilization for greater than one year and two had stabilization greater than two years.  In seven patients, liver function improved and in 15 patients the undercarboxylated prothrombin normalized.


Carr BI.  Suppression of DCP/PIVKA-2 and alpha-fetoprotein levels in human hepatocellular carcinoma (HCC) by high doses of vitamin K1 (VK1).  Hepatology.  1996;348A.


Fraga CG, Motchnik PA, Wyrobek AJ, Rempel DM, Ames BN.  Smoking and low antioxidant levels increase oxidative damage to sperm DNA.  Mutat Res.  1996 Apr 13;351(2):199-203. 

Smoking and low antioxidant levels increase oxidative damage to sperm DNA.  They discuss the possibility that paternal smoking causes mutations in sperm that lead to cancer, birth defects, and genetic diseases in offspring.


Jie KG, Bots ML, Vermeer C, Witteman JC, Grobbee DE.  Vitamin K status and bone mass in women with and without aortic atherosclerosis:  a population-based study.  Calcif Tissue Int.  1996 Nov;59(5):352-6.

Increasing evidence indicates that Gla-proteins are involved in the regulation of calcification processes in both bone tissue and atherosclerotic vessel wall.  This study showed that women with atherosclerotic calcifications had a 7% lower bone mass.  No differences were observed for parathyroid hormone and vitamin D levels.  It was concluded that the atherosclerotic women in this study may be at higher risk of osteoporotic fractures as evidenced by their lower bone mass and higher serum irOc free levels.  It appears that vitamin K status affects the mineralization processes in both bone and in atherosclerotic plaques.


Kelsey JL, Bernstein L.  Epidemiology and prevention of breast cancer.  Ann Rev Public Health.  1996;17:47-67.


Bendich A, Mallick R, Leader S.  Potential health economic benefits of vitamin supplementation.  West J Med.  1997 May;166(5):306-312. 

Based on published risk reductions and annual hospital charges for birth defects, low birth weight premature births, and coronary heart disease could be reduced by about 40, 60, and 38%, respectively.  For the conditions studied, nearly $20 billion in hospital charges were potentially avoidable with daily use of folic acid- and zinc- containing multivitamins by all women of childbearing age and daily vitamin E supplementation by those over age 50.  There are benefits to supplementation, in addition to direct savings of medical costs, including the mitigated human consequences of improved health. 


Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, et al.  Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage:  implications for cancer and neuronal damage.  Proc Natl Acad Sci USA.  1997;94:3290-3295. 

A significant proportion of the US population has low folate levels.  Folate deficiency is one of the most common vitamin deficiencies, occurring in approximately 10% of the US population, in nearly half of low income elderly and in adolescents.  Such breaks could contribute to the increased risk of cancer and cognitive defects associated with folate deficiency in humans.  Folate deficiency is associated with increased risk of colon, esophageal, and cervical cancer, and can induce extensive chromosome damage.


Huang Z, Hankinson SE, Colditz GA, Stampfer MJ, Hunter DJ, Manson JE, et al.  Dual effects of weight and weight gain on breast cancer risk.  JAMA.  1997;278(17):1407-1411.

 

Rice-Evans CA, Sampson J, Bramley PM, Holloway DE.  Why do we expect carotenoids to be antioxidants in vivo?  Free Radic Res.  1997 Apr;26(4):381-98. 


Sasaki I, Hashimoto S, Hoda M, Hida T, Ohsawa S, Nakajo S, et al.  Novel role of vitamin K2:  a potent inducer of differentiation of various human myeloid leukemia cells lines.  Biochem Biophys Res Commun.  1994;205:1305-1310.

This study found that vitamin K2 could safely be used in differentiation therapy on leukemia cell lines.  In contrast to VK1 which had no effect. 


Scholl TO, Hediger ML, Bendich A, Schall, JI, Smith WK, Krueger PM.  Use of multivitamin/mineral prenatal supplements:  influence on the outcome of pregnancy.  Am J Epidemiol.  1997 Jul 15;146(2):134-41. 

This study examined the association of prenatal multivitamin/mineral supplement use during the first and second trimesters of pregnancy by low income, urban women.  They found that the use of prenatal multivitamin/mineral supplements may have the potential to diminish infant morbidity and mortality, as the risk for very preterm delivery was reduced more than fourfold. 

 

Woodall AA, Ames BN.  Nutritional prevention of DNA damage to sperm and consequent reduction in birth defects and cancer in offspring.  In: Bendich A, Deckelbaum R, editors.  Preventive Nutrition.  Totowa NJ: The Humana Press, Inc. 1997. P 373-385.


Yaguchi M, Miyazawa K, Katagiri T, Nishimaki J, Kizaki M, Tohyama K, et al.  Vitamin K2 and its derivatives induce apoptosis in leukemia cells and enhance the effect of all-trans retinoic acid.  Leukemia.  1997 Jun;11(6):779-87.

Menaquinone 3, 4 and 5 and phylloquinone were examined for their apoptosis inducing ability on leukemia cells in vitro.  The menaquinones showed a potent apoptosis inducing ability, while phylloquinone showed no effect on any of the leukemia cells.  The data suggest the possibility of using VK2 for the treatment of leukemais.


Ames BN.  Micronutrients prevent cancer and delay aging.  Toxicol Lett.  1998 Dec 28;102-103:5-18. 

At least 40 micronutrients are required in the human diet.  Deficiency of vitamins B12, folic acid, B6, niacin, C or E, or iron or zinc appears to mimic radiation in damaging DNA by causing single and double-strand breaks, oxidative lesions, or both.  The percentage of the US population that has a low intake, defined as less than 50% of the RDA for each of these eight micronutrients ranges from 2% to 20%; half of the population may be deficient in at least one of these micronutrients.  Micronutrient deficiency may explain why the quarter of the population that eats the fewest fruits and vegetables has approximately double the cancer rate for most types of cancer when compared to the quarter with the highest intake.  80% of American children and adolescents and 68% of adults do not eat five portions a day. 

 

Beckman KB, Ames BN.  The free radical theory of aging matures.  Physiol Rev.  1998 Apr;78(2):547-81.

Several lines of evidence have convinced scientists that oxidants play an important role in aging.  Vitamin K has potent antioxidant activity.


Caan B, Quesenberry CP Jr, Coates AO.  Differences in fertility associated with caffeinated beverage consumption.  Am J Public Health.  1998 Feb;88(2):270-4.


Fujita H, Tomiyama J, Tanaka T.  Vitamin K2 combined with all-trans retinoic acid induced complete remission of relapsing acute promyelocytic leukaemia.  Br J Haematol.  1998 Nov;103(2):58405.


Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA, et al.  Multivitamin use, folate, and colon cancer in women in the Nurses’ Health Study.  Ann Intern Med.  1998 Oct 1;129(7):517-24.

High intake of folate may reduce the risk for colon cancer.  They studied over 88,000 women from the Nurses’ Health Study who were free of cancer in 1980, and provided updated assessment of diet, including multivitamin supplement use, from 1980 to 1994.  They found that the long-term use of multivitamins may substantially reduce the risk of colon cancer.  Folate from dietary sources alone was related to a modest reduction in risk for colon cancer, and the benefit of long-term multivitamin use was present across all levels of dietary intakes. 


Oakley GP, Jr.  Eat right and take a multivitamin.  N Engl J Med.  1998;338:1060-1061.

Breakfast cereal fortified with folic acid was associated with a reduction of plasma homocysteine levels with patients who had coronary heart disease.


Yaguchi m, Miyazawa K, Otawa M, Katagiri T, Nishimaki J, Uchida Y, et al.  Vitamin K2 selectively induced apoptosis of blastic cells in myelodysplasticc syndrome:  flow cytometric detection of apoptosis cells using APO2.7 monoclonal antibody.  Leukemia 1998;12:1392-1397.

VK2 has a potent apoptosis-inducing effect on leukemia cells in patients.  Studied bone marrow from patients with MDS and Leukemia.  VK2 (MK3, MK4 and MK5) potently induced apoptosis of leukemic blast cells compared with untreated control cells in all 15 MDS patients tested.


Zaniboni A, Biasi L, Graffeo M, et al.  Phase II study of high-dose vitamin K1 in hepatocellular carcinoma: a GISCAD study.  ASCO 1998;17:1182.

A phase II study of 14 HCC patients employed oral vitamin K (Konakion, 20 mg) twice daily until the disease progressed.  Nine patients were evaluable.  Four patients of the nine were reported to have stable disease, while five progressed.  No toxicity was found in any of the participants.


Makomaski Illing EM & Kaiserman MJ.  Mortality attributable to tobacco use in Canada and its regions, 1994 and 1996.  Chronic Dis Can.  1999;20(3):111-7.

The data from the database indicate that 29,229 men and 15,986 women died in 1996 as a result of smoking and the increase in female mortality is almost entirely due to adult diseases, with the largest percentage attributable to cancer.


Nishimaki J, Miyazawa K, Yaguchi Mi, Katagiri T, Kawanishi Y, Toyama K, et al.  Vitamin K2 induces apoptosis of a novel cell line established from a patient with myelodysplastic syndrome in blastic transformation.  Leukemia.  1999 Sep;13(9):1399-405.

 

Olson RE.  Vitamin K.  In:  Shils ME, Olson JA, Shike M, Ross AC, ed.  Modern nutrition in health and disease, 8th ed.  Philadelphia:Lea and Febiger, 1999;363-380.


Schurgers LJ, Geleijnse JM, Grobbee DE, Pols HAP, Hofman A, Witteman JCM, et al.  Nutritional intake of vitamins K1 (phylloquinone) and K2 (menaquinone) in the Netherlands.  J Nutr Environ Med.  1999;9:115-22.

Other tissues, (bone, vessel wall) were shown to produce vitamin K-dependent proteins not involved in blood coagulation.  Multiple forms of vitamin K have been found in human food; phylloquinone and various menaquinones.  A recommended daily allowance (RDA) has only been defined for K1, and its value is exclusively based on blood clotting data.  In this study, they prepared a provisional table of menaquinones in food, which have been used to calculate the total vitamin K intake in a well defined cohort of the Dutch population  and concluded that K1 is the major form of nutritional vitamin K, and that total vitamin K intake is higher than in other populations.  They suggest that present RDA values be reconsidered.                                                                   

 

Sun L, Yoshii Y, Miyagi K, Ishida A.  Proliferation inhibition of glioma cells by vitamin K2.  No Shinkei Geka. 1999;27:119-125.


Takami A, Nakao S, Ontachi Y, Yamauchi H, Matsuda T.  Successful therapy of myelodysplastic syndrome with menatetrenone, a vitamin K2 analog.  Int J Hematol.  1999;69:24-26. 

Although VK2 is an inducer of differentiation of leukemic cell lines, its clinical efficacy in the treatment of MDS in unclear.  In this study, VK2 (MK4) was administered at 45 mg daily to an 80 year old woman with MDS, (refractory anemia). The patient’s pancytopenia (a deficiency of all types of blood cells, including white, red and platelets, produced by the bone marrow) gradually improved  and she became transfusion independent after 14 months.  Pacytopenia recurred when menatetrenone was discontinued but recovered again with readministration.  Administration of menatetrenone at a dose effective in improving osteoporosis may also be useful in restoring hematopoiesis in MDS patients. 

 

Yaguchi M, Miyazawa K, Otawa M, Ito Y, Kawanishi Y, Toyama K.  Vitamin K2 therapy for a patient with myelodysplastic syndrome.  Leukemia.  1999 Jan;13(1):144-5.

 

2000s

American Cancer Society.  2014.  What kids of illness and death are caused by smoking cigars?  American Cancer Society.  2014 [cited 2014 May 19]; Available from: http://www.cancer.org/cancer/cancercauses/tobaccocancer/cigarsmoking/cigar-smoking-cancer-and-health

 

Henderson BE, Feigelson HS.  Hormonal carcinogenesis.  Carcinogenesis.  2000 Mar;21(3):427-33.

Hormone-related cancers, namely breast, endometrium, ovary, prostate, testis, thyroid and osteosarcoma, share a unique mechanism of carcinogenesis.  Endogenous and exogenous hormones drive cell proliferation, and thus the opportunity for the accumulation of random genetic errors. 

 

Kant AK.  Consumption of energy-dense, nutrient-poor foods by adult Americans:  nutritional and health implications.  The Third National Health and Nutrition Examination Survey, 1988-1994.  Am J Clin Nutr.  2000;72:929-936.

Dietary guidelines recommend limiting the intake of energy-dense, nutrient poor (EDNP) foods, and this study studied the consumption patterns of these foods.  The associations of EDNP food intake with intakes of energy, macronutrients, micronutrients, and serum vitamin, lipid and carotenooid profiles were examined.  The results suggest that EDNP foods were consumed at the expense of nutrient dense foods, resulting in increased risk of high energy intake, marginal micronutrient intake, poor compliance with nutrient and food group dietary guidance, and low serum concentrations of vitamins and carotenoids.

 

 Lamson DW, Brignall MS.  Antioxidants and cancer, part 3: quercetin.  Altern Med Rev.  2000 Jun;5(3):196-208.

Quercetin is a potential anti-cancer agent, including cell cycle regulation.  It appears to have little toxicity when administered orally or intravenously.  Preliminary data suggests it inhibits tumor growth.  More research is needed to explore the anti-cancer effect.

 

Lykkesfeldt J, Christen S, Wallock LM, Chang HH, Jacob RA, Ames BN.  Ascorbate is depleted by smoking and repleted by moderate supplementation:  a study in male smokers and nonsmokers with matched dietary antioxidant intakes.  Am J Clin Nutr.  2000 Feb;71(2):530-6.

 

Miyakawa T, Kajiwara Y, Shirahata A, Okamoto K, Itoh H, Ohsato K.  Vitamin K contents in liver tissue of hepatocellular carcinoma patients.  Jpn J Cancer Res.  2000 Jan;91(1):68-74.

Serum protein induced in vitamin K absence-II (PIVKA-II) is used as a tumor marker because it increases at a notably higher rate in patients with hepatocellular carcinoma.  To clarify the mechanism causing the elevation of serum PIVKA-II, we measured the contents of vitamins K1 and K2 (MK4, MK5, Mk6, MK7, MK8, MK9, and MK10) in liver tissue from 21 patients with HCC.  Vitamin K1, MK7, MK8 and MK10 were significantly lower than that found in noncancerous tissue.  It appears that there is a vitamin K deficiency in cancerous tissue of the liver.

 

Miyazawa K, Nishimaki J, Ohyashiki K, Enomoto S, Kuriya S, Fukuda R, et al.  Vitamin K2 therapy for myelodysplastic syndromes (MDS) and post-MDS acute myeloid leukemia:  information through a questionnaire survey of multi-center pilot studies in Japan.  Leukemia.  2000 Jun;14(6):1156-57.

 

Platz EA, Hankinson SE, Hollis BW, Colditz GA, Hunter DJ, Speizer FE, et al.  Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and adenamatous polyps of the distal colerectum.  Cancer Epidemiol Biomarkers Prev.  2000a;9:1059-65.

Vitamin D inhibits proliferation and promotes differentiation of human colon cancer cell lines.  This study evaluated the relationship of plasma with colorectal adenoma in matched groups from the Nurses’ Health Study.  They concluded that women who have low levels of circulating vitamin D may be at higher risk of distal colorectal adenomas.

 

Platz EA, Rimm EB, Willett WC, Kantoff PW, Giovannucci E.  Racial variation in prostate cancer incidence and in hormonal system markers among male health professionals.  J Natl Cancer Insti.  2000b;92:2009-17.

This study confirms the elevated incidence of prostate cancer among African Americans and show that it is not explained by differences in the distribution of possible dietary and lifestyle risk factors.  Part of the incidence is related to a racial variation in the length of the androgen receptor gene, among African American men.

 

Ries LA, Wingo PA, Miller DS, Howe HL, Weir HK, Rosenberg HM, et al.  The annual report to the nation on the status of cancer, 1793-1997, with a special section on colorectal cancer.   Cancer.  2000 May 15;88(10):2398-424.

 

Schurgers LJ, Vermeer C.  Determination of phylloquinone and menaquinones in food.  Effect of food matrix on circulating vitamin K concentrations.  Haemostasis.  2000 Nov-Dec;30(6):298-307.

They investigated the effect of the food matrix on vitamin K bioavailability using 6 healthy male volunteers.  They found that the absorption of pure K1 was faster than that of food bound vitamins.  Moreover, circulating K2 concentrations after the consumption of natto were about 10 times higher than those of K1 after eating spinach.  It was concluded that the contribution of K2 vitamins to the human vitamin K status is underestimated.

 

Sun Lk, Yoshii Y, Miyagi K.  Cytotoxic effect through Fas/APO-1 expression due to Vitamin K in human glioma cells.  J Neurooncol.  2000;47:31-38.

They investigated the mechanisms of vitamin K in inhibiting growth in glioma (brain cancer) cells.  They used vitamin K1, K2, and K3.  They concluded that VK3 induced apoptosis by promoting the generation of intracellular ROI and Fas/APO-1 expression, and that VK2 induced apoptosis by some other unknown pathway.


Ames BN.  DNA damage from micronutrient deficiencies is likely to be a major cause of cancer.  Mutat Res.  2001 April 18;475(1-2):7-20. 

This study reviews some of the more well known micronutrients including folic acid, B12, B6, niacin, C, E, iron and zinc and how a deficiency can mimic the effect of radiation by damaging DNA, causing single and double strand breaks, oxidative lesions, or both.  For example, folate deficiency leads to chromosome breaks, and was present in approximately 10% of the US population, and in a much higher percentage of the poor.  Micronutrient deficiency may explain, in good part, why the quarter of the population that eats the fewest fruits and vegetables (five portions is advised) has about double the cancer rate for most types of cancer when compared to the quarter with the highest intake.  Common micronutrient deficiencies are likely to damage DNA by the same mechanism as radiation.  Remedying micronutrient deficiencies should lead to a major improvement in health and an increase in longevity at low cost.

 

Crott JW, Mashiyama ST, Ames BN, Fenech MF.  The effect of folic acid deficiency and a genetic polymorphism on chromosome damage in human lymphocytes in vitro.  Cancer Epidemiol Biomarkers Prev. 2001b;10:1089-1096.

They studied the effects of in vitro folic acid deficiency on primary human lymphocytes.  The results showed that a certain genetic polymorphism does not affect the ability of a cell to resist chromosome damage induced by folic acid deficiency.

 

Fenech M, Ferguson LR.  Vitamins/minerals and genomic stability in humans.  Mutat Res.  2001 Apr 18;475(1-2):1-6.

Recommended daily allowances (RDAs) of micronutrients have been traditionally derived as those levels necessary to prevent symptoms of deficiency diseases.  There is increasing evidence that higher levels of many such micronutrients may be necessary for various DNA maintenance reactions, and that the current RDAs for some micronutrients may be inadequate.  14 mini-reviews summarize the role of specific micronutrients in various aspects of DNA maintenance:  synthesis, repair, methylation, gene mutation, chromosome breakage, chromosome segregation, gene expression , oxidative stress, necrosis and apopotosis.   These reviews are an essential step towards a definition of RDAs designed to maintain genomic stability.  Micronutrients may be essential to prevent degeneratiave diseases including cancer. 

 

 Levine AJ, Harper JM, Ervin CM, Chen YH, Harmon E, Xue S, et al.  Serum 25-hydroxyvitamin D, Dietary calcium intake, and distal colorectal adenoma risk.  Nutr Cancer.  2001;39:35-41.

Vitamin D has recently emerged as a potentially protective agent against colorectal neoplasia

 

Miyazawa K, Yaguchi M, Funato K, Gotoh A, Kawanishi Y, Nishizawa Y, et al.  Apoptosis/differentiation –inducing effects of vitamin K2 on HL-60 cells:  dichotomous nature of vitamin K2 in leukemia cells.  Leukemia.  2001 Jul;15(7):1111-7.

This study showed that VK2 shows differentiation-inducing effects on leukemia cells which are resistant against VK2-inducing apoptosis.  The dichotomous nature of VK2 against leukemia cells appears to have clinical benefits for treating patients with leukemias and myelodysplastic syndromes.

 

National Academy of Sciences. Dietary Reference Intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, nickel, silicon, vanadium, and Zinc.  National Academy of Science; 2001 [cited 2014 May 37.  Available from http://fnic.nal.usda.gov/dietary-guidance/dri-reports/vitamin-vitamin-k-arsenic-boron-chromium-copper-iodine-iron-manganese#overlay-context=dietary-guidance/dri-reports/thiamin-riboflavin-niacin-vitamin-b6-folate-vitamin-b12-pantothenic

 

Nathanson KN, Wooster R, Weber BL.  Breast cancer genetics:  what we know and what we need.  Nat Med.  2001;7:552-556.

Okayasu H, Ishihara M, Satoh K, Sakagami H.  Cytotoxic activity of vitamins K1, K2 and K3 against human oral tumor cell lines.  Anticancer Res.  2001 Jul-Aug;21(4A):2387-92.

Vitamin K1, K2 and K3 were compared for their cytotoxic activity, radical generation and O2-scavenging activity.  Vitamin K3 showed the highest cytotoxic activity against human oral tumor cell lines, leukemic cell lines and others.  The cytotoxic activity of vitamins K2 and K1 was one and two orders lower, respectively, than K3.  The data suggest that vitamin K3 is cytotoxic and has two opposing actions, both antioxidant and prooxidant, depending on the experimental conditions.

 

Osada S, Carr BI.  Mechanism of novel vitamin K analog induced growth inhibition in human hepatoma cell line.  J Hepatol.  2001 May;34(5):676-82.

 

Patterson RE, Kristal AR, and Heuhouser ML.  Vitamin supplements and cancer risk: epidemiologic research and recommendations.  In:   Bendich A, Deckelbau RJ, editors.  Primary and secondary preventive nutrition.  Totowa NJ:Humana Press;2001.  p 21-41. 

Few reports to date have addressed supplemental nutrients directly.  These studies offer insight into effects of nutrients that are distinguishable from effects of other biologically active compounds in foods.  Randomized clinical trials have found protective effects of alpha-tocopherol against prostate cancer, mixtures of retinol/zinc and beta-carotene/alpha-tocopherol/selenium against stomach cancer and selenium against total, lung, and prostate cancers.  Case-control studies have reported an inverse association between bladder cancer and vitamin C, oral/pharyngeal cancer and supplements and several cancers and vitamin E.  Future studies of supplements and cancer appear warranted.

 

Vainio H, Bianchini F.  Physical activity and cancer prevention – is ‘no pain, no gain’ passé?  Eur J Cancer Prev.  2001 Aug;10(4):301-2. 

 

Wakimoto P, Block G.  Dietary intake, dietary patterns, and changes with age:  an epidemiological perspective.  J Gerontol A Biol Sci Med Sci.  2001;56(S2):65-80.

Dietary intake changes with age.  Substantial numbers of older Americans consume only one fifth to one third of the recommended dietary allowance.  There is evidence of an age-related decline in absorptive and metabolic function, increasing their potential for nutritional deficiency.  With the aging of the population, more research is needed on nutrient requirements and health outcomes.

 

Willett WC, Stampfer MJ.  What vitamin should I be taking doctor?  N Engl J Med.  2001;345:1819-1824.

Given the greater likelihood of benefit than harm, and considering the low cost, they recommend that a daily multivitamin makes sense for most adults.  Substantial data suggests that higher intakes of vitamins will benefit many people.  Many multivitamins also include essential minerals.  However, vitamins are no substitute for a healthy lifestyle or diet, because foods contain additional important components, such as fiber and essential fatty acids. 

 

Abe Y, Muta K, Hirase N, Choi I, Matsushima T, Hara K, et al. Vitamin K2 therapy for myelodysplastic syndrome.  Rinsho Ketsueki.  2002 Feb;43(2):117-21.

Vitamin K2 is reported to induce apoptosis or differentiation of leukemic cell lines in vitro.  In this study they gave a vitamin K, specifically, MK4, at 45 mg daily to 23 patients with MDS.  Six patients showed improvement of anemia.  No adverse effect of VK2 was observed and the time required to obtain the hematological response was short, being 3 months on average.  They concluded that VK2 therapy has potential as a treatment for patients with MDS.


Abrams SA.  Nutritional rickets:  an old disease returns.  Nutr. Rev.  2002 Apr;60(4):111-5.

Nutritional rickets, an ancient disease that was thought to have been cured has made an unexpected comeback, apparently related to low dietary intake of vitamin K and calcium and decreased sunshine exposure.

 

Albitar M, Manshouri T, Shen Y, Liu D, Beran M, Kantarjian HM, et al.  Myelodysplastic syndrome is not merely “preleukemia”.  Blood.  2002 Aug 1;100(3):791-8.


Ames BN, Elson-Schwab I, & Silver E A.  High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased Km):  relevance to genetic disease and polymorphisms 1, 2, 3.  Am J Clin Nutr.  2002 Apr;75(4):616-658.

As many as one third of mutations in a gene result in the corresponding enzyme having a decreased binding affinity, resulting in a lower rate of reaction.  So far, at least 50 human genetic diseases due to defective enzymes can be remedied or ameliorated by the administration of high doses of the vitamin component of the corresponding coenzyme, which at least partially restores enzymatic activity.  The proportion of mutations in a disease gene that is responsive to high concentrations of a vitamin or substrate may be one third or greater, indicating that vitamin therapy may be a simple, obvious remedy.

 

Ames BN, Wakimoto P.  Are vitamin and mineral deficiencies a major cancer risk?  Nat Rev Cancer.  2002 Sep;2(9):694-704.

Diet is estimated to contribute to about one-third of preventable cancers – about the same amount as smoking.  Experimental evidence indicates that vitamin and mineral deficiencies can lead to DNA damage.  Optimizing vitamin and mineral intake by encouraging dietary change, multivitamin and mineral supplements, and fortifying foods might therefore prevent cancer and other chronic diseases. 

 

Bianchini F, Kaaks R, Vainio H.  Overweight, obesity, and cancer risk.  Lancet Oncol.  2002 Sep;3(9):565-74.

Over the past decades the proportion of people with excess body weight has been increasing in both developed and less developed countries.  In addition to the risk of cardiovascular disease and type II diabetes, the evidence shows that excess body weight is directly associated with risk of cancer at several organ sites, including colon, breast (in postmenopausal women), endometrium, esophagus, and kidney.  These associations with cancer risk may be explained by alterations in the metabolism of endogenous hormones, including sex steroids, insulin, and insulin like growth factors which can lead to distortion between the balance of cell proliferation, differentiation and apoptosis. 

 

Olshan AF, Smith JC, Bondy ML, Neglia JP, Pollock BH.  Maternal vitamin use and reduced risk of neuroblastoma.  Epidemiology.  2002 Sep;13(5):575-80. 

They investigated maternal vitamin use and neuroblastoma in offspring, and found that daily vitamin and mineral use in the month before pregnancy and in each trimester was associated with a 30-40% reduction in the risk of neuroblastoma.  This finding is consistent with findings for other childhood cancers.

 

Fairfield KM, Fletcher RH.  Vitamins for chronic disease prevention in adults:  scientific review.  JAMA.  2002;287:3116-3126.

Inadequate intake of several vitamins is associated with chronic disease, such as coronary heart disease, cancer and osteoporosis.  This study reviewed vitamins with regard to their biological effects, food sources, deficiency syndromes, potential for toxicity, and relationship to chronic disease.  Elderly people, vegans, alcohol-dependent individuals, and patients with malabsorption are at higher risk of inadequate intake or absorption of several vitamins. 

 

Fitzpatrick FA.  Inflammation, carcinogenesis and cancer.  Int Immunopharmacol.  2001 Sep; 1(9-10):1651-67.

 

Gold LS, Slone TH, Manley NB, Ames BN.  Misconceptions about the causes of cancer.  Vancouver, BC, Canada:  The Fraser Institute.  2002.

Cancer is due, in part, to normal aging and increases exponentially with age in both rodents and humans.  Aging and its degenerative diseases appear to be due in part to oxidative damage to DNA and other macromolecules.  Byproducts of normal metabolism – superoxide, hydrogen peroxide and hydroxyl radical are the same oxidative mutagens produced by radiation.  Antioxidant defenses against oxidative damage include vitamin C, and vitamin D.  Mitochondria may need different antioxidants.

 

Hagen TM, Moreau R, Suh JH, Visioli F.  Mitochondrial decay in the aging rat heart: evidence for improvement by dietary supplementation with acetyl-L-carnitine and/or lipoic acid.  Ann NY Acad Sci.  2002b;959:491-507.

It is postulated that mitochondrial decay is a significant underlying part of the aging process.  Decline in mitochondrial function may lead to cellular energy deficits, especially in times of greater energy demand, and may compromise vital cellular operations, including detoxification, repair systems, DNA replication, and osmotic balance.  Mitochondrial decay may also render the cell more prone to oxidative insult.  And maintenance of mitochondrial function may be important to maintain overall myocardial function.  Two supplements, ALCAR, and R-alpha-lipoic acid may improve myocardial bioenergetics and lower the increased oxidative stress associated with aging. 

 

Ho E, Ames BN.  Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFkB, and AP1 DNA-binding, and affects DNA repair in a rat glioma cell line.  Proc Natl Acad Sci USA.  2002;99:16770-16775. 

Approximately 10% of the US population ingests 0% of the current recommended daily allowance for zinc.  This study found that low intracellular zinc status causes oxidative DNA damage and induces DNA-repair protein expression, and that the binding of p53 and that important downstream signals leading to proper DNA repair are lost without zinc.

 

Holt PR, et al.  Colonic epithelial cell proliferation decreases with increasing levels of serum 25-hydroxy vitamin D.  Cancer Epidemiol Biomarkers Prev.  2002;11:113-119.

Epidemiological evidence suggests a potential role for vitamin D in colon cancer prevention.  Vitamin D, absorbed from the intestine or derived from solar ultraviolet, is metabolized in the liver.  It was thought that vitamin D was metabolized in the kidney, but more recent studies have shown that it can occur in other tissues.  This study indicated that vitamin D may have an important role in determining the effects of calcium on colorectal epithelial proliferation.

 

IARC Working Group.  Some traditional herbal medicine, some mycotoxins, naphthalene and styrene.  IARC monographs on the evaluation of carcinogenic risks to humans (IARC Scientific Publications No. 82), Lyon, IARC.  2002;82:1-590.

 

Jancin B.  Vitamin K cuts hepatocellular CA mortality.  Fam Pract News.  2002:32 16.

A common event that heralds greatly diminished survival in hepatocellular cancer is portal vein invasion.  121 patients with HCC were randomized to receive oral vitamin K, 1145 mg/day or not.  All patients received conventional therapy as well.  In the treatment group, the rate or portal vein invasion at 12 months follow up was 2% in VK2 recipients and 23 % in controls.  At two years, portal vein invasion was present in 23% of the VK2 group and 47% of controls.  There isn’t a lot to offer patients with liver cancer and this new treatment may significantly prolong survival. 

 

Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, et al.  Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation:  partial reversal by feeding acetyl-L-carnitine and/or R- α-lipoic acid.  Proc Natl Acad Sci USA.  2002;99:2356-2361.

Accumulation of oxidative damage to mitochondria, protein, and nucleic acid in the brain may lead to neuronal and cognitive dysfunction.  The effects on cognitive function, brain mitochondrial structure, and biomarkers of oxidative damage were studied after feeding old rats two mitochondrial metabolites, ALCAR, and or LA in diet.  Performance on memory tasks was improved by lowering oxidative damage and improving mitochondrial function. The results suggest that mitochondrial metabolites may delay brain aging and age-associated neurodegenerative diseases.

 

Osler M, Tjonneland A, Suntum M, Thomsen BL, Stripp C, Gronbaek M, et al.  Does the association between smoking status and selected healthy foods depend on gender?  A population-based study of 54,417 middle-aged Danes.  Eur J Clin Nutr.  2002 Jan;56(1):57-63.

 

Schurgers LJ, Vermeer C.  Differential lipoprotein transport pathways of K-vitamins in healthy subjects.  Biochim Biophys Acta.  2002 Feb 15;15700(1):27-32.

Vitamin is a group name for K1 (phylloquinone) and K2 (menaquinones).  Both contribute to the vitamin K status of tissue.  Following intestinal absorption, these compounds are transported to their target tissues via lipoproteins.  K1 is preferentially accumulated in the liver, whereas menaquinones have a more widespread distribution pattern.  In this study they tested whether the differences are explained by different liposolubility of the various K vitamers.  Results indicate that most K vitamins are transported to the liver.  Both menaquinones , MK4 and MK9, were also found in triglyceride rich lipoproteins and low density lipoproteins, where MK2 was present also in high density lipoproteins.  MK9 had a very long half life in circulation, suggesting it may be a more constant source of vitamin K than either K1 or MK4.

 

Sturm R.  The effects of obesity, smoking, and drinking on medical problems and costs.  Health Aff (Millwood).  2002;21:245-53. 

This study compares the effects of obesity, overweight, smoking, and problem drinking on health care use and health status based on national survey data.  Obesity has roughly the same association with chronic health conditions as does twenty years’ aging; this greatly exceeds the associations of smoking or problem drinking.  Obesity is associated with a 36 percent increase in inpatient and outpatient spending and a 77 percent increase in medications, compared with a 21 percent increase in inpatient and outpatient spending and a 28 percent increase in medications for current smokers and smaller effects for problem drinkers. 

 

Pereira MA, Jacobs DR Jr.  Van Horn L, Slattery ML, Karashov AI, Ludwig DS.  Dairy consumption, obesity, and the insulin resistance syndrome in young adults:  the CARDIA Study.  JAMA.  2002;287:2081-2089.

Components of the insulin resistance syndrome (IRS) which includes obesity, glucose intolerance, hypertension, and dyslipidemia, are major risk factors for type 2 diabetes and heart disease.  This study examined the associations between dietary intake and incidence of IRS, adjusting for lifestyle and dietary factors.  The results indicated that dairy consumption was inversely associated with the incidence of IRS components among overweight individuals.  Every daily occasion of dairy consumption was associated with 21% lowers odds of IRS. 


Vijayalaxmi, Thomas CR Jr, Reiter RJ, Herman TS.  Melatonin: from basic research to cancer treatment clinics.  J Clin Oncol.  2002 May 15;20(10):2572-601.

Melatonin is the chief product of the pineal gland and is a direct free radical scavenger, an indirect antioxidant and an important modifier of the immune system.  In past research, melatonin protected healthy cells from radiation-induced and chemotherapeutic drug-induced toxicity.  This study summarizes the evidence regarding the potential use of melatonin in cancer treatment.


Walter PB, Knutson MD, Paler-Martinez A, Lee S, Xu Y, Viteri FE, et al.  Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats.  Proc Natl Acad Sci USA.  2002;99:2264-2269.

Approximately two billion people, mainly women and children, are iron deficient.  Two studies examined the effects of iron deficiency and supplementation on rats, and found that iron deficient rats had lower liver mitochondrial respiratory control ratios and increased levels of oxidants.  Study 2 found that iron deficient rats given high doses of iron had less mitochondrial DNA damage.  Both inadequate and excessive iron causes significant mitochondrial malfunction.  Untreated iron deficiency as well as excessive iron supplementation, are deleterious and emphasize the importance of maintaining optimal iron intake. 


Aisen PS, Egelko A, Andrews H, Diaz-Arrastia R, Weiner M, DeCarli C, et al., A pilot study of vitamins to lower plasma homocysteine levels in Alzheimer disease.  Am J Geriatr Psychiatry.  2003 Mar-Apr;11(2):246-49.   

People with elevated levels of homocysteine have nearly double the risk of developing Alzheimer’s disease.  High dose vitamin supplementation, folic acid, vitamin B12 and vitamin B5 for eight weeks, reduces homocysteine levels in patients with Alzheimer disease, making the case for the proper diet and vitamins. 


Ames BN.  The metabolic tune-up:  metabolic harmony and disease prevention.  J Nutr.  2003 May; 133(5 Suppl 1):1544S-8S).

An optimum intake of micronutrients and metabolites, which varies with age and genetic constitution, would tune up metabolism and give a marked increase in health, particularly for the poor and elderly at little cost. 


Barringer TA, Kirk JK, Santaniello AC, Foley KL, Michielutte R.  Effect of a multivitamin and mineral supplement on infection and quality of life.  A randomized, double-blind, placebo-controlled trial.  Ann Intern Med.  2003 Mar 4;138(95):365-71.

A randomized, double-blind, placebo-controlled trial was conducted on adults age 45 to 64 years with type 2 diabetes.  The multivitamins and mineral supplements or placebos were taken daily for one years.  The results indicated that the participants receiving a placebo reported more infectious illnesses over the study year, 73% to 43%.   Infection related absenteeism was also significantly higher in the placebo group than in the treatment group (57% vs 21%).  Among the diabetic participants receiving placebo, 93% reported an infection compared with 17% of those receiving supplements


Braam LA, Knapen MH, Geusens P, Brouns F, Hamulyak K, Gerichhausen MJ, et al.  Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age.  Calcif Tissue Int.  2003 Jul;73(1):21-6.


Church TS, Earnest CP, Wood KA, Kampert JB.  Reduction of C-reactive protein levels through use of a multivitamin.  Am J Med.  2003 Dec 15;115(9):702-7. 

Elevated C-reactive protein levels are associated with the risk of cardiovascular disease and diabetes.  This study examined whether multivitamins reduce C-reactive protein levels in a double-blind, placebo-controlled trial.  The results indicated that at six months, C-reactive protein levels were significantly lower in the multivitamin group.   


Fenech M.  Nutritional treatment of genome instability:  a paradigm shift in disease prevention and in the setting of recommended dietary allowances.  Nutri Res Revs.  2003;16:109-122.

They discuss the concept of recommended dietary allowances for genome stability and how this could be achieved within the emerging field of nutritional genomics.  They discuss a vision for a disease-prevention strategy based on the diagnosis and nutritional treatment of genome instability, i.e. “Genome Health Clinics”. 


Ho E, Courtemanche C, Ames BN.  Zinc deficiency induces oxidative DNA damage and increases -53 expression in human lung fibroblasts.  J Nutr.  2003;133:2543-2548.

Poor zinc nutrition may be an important risk factor in oxidant release and the development of DNA damage and cancer.  Approximately 10% of the United States population ingests <50% of the recommended daily allowance for zinc, a cofactor in proteins involved in antioxidant defenses, electron transport, DNA repair and p53 protein expression.  This study examined the effects of zinc deficiency.  Zinc deficiency caused oxidative stress and DNA damage, and also compromised the cells’ ability to repair this damage.  Zinc adequacy appears to be necessary for maintaining the DNA integrity and may be important in the prevention of DNA damage and cancer.

Holmquist C, Larsson S, Wolk A, de Faire U.  Multivitamin supplements are inversely associated with risk of myocardial infarction in men and women –Stockholm Heart Epidemiology Program (SHEEP).  J Ntr.  2003 Aug;133(8):2650-4. 

They examined the association between self-selected use of low dose multivitamin supplements and the risk of myocardial infarction (MI), based on data from a large population-based, case-controlled study of subjects aged 45-70 residing in Sweden, a country in which consumption of fruits and vegetables is low and foods are not fortified with folic acid. The findings indicated that the use of a low dose multivitamin supplement was associated with a substantially lower risk of nonfatal myocardial infarctions.  


Jacobs EJ, Connell CJ, Chao A, McCullough ML, Rodriguez C, Thun MJ, Callee EE.  Multivitamin use and colorectal cancer incidence in a US cohort:  does timing matter?  Am J Epidemiol.  2003 Oct 1;158(7):621-28. 

Multivitamins contain several nutrients, including folic acid, that are hypothesized to reduce the risk of colorectal cancer.  This study looked at the association between regular multivitamin use (four or more times per week) and colorectal cancer incidence among 145,260 men and women in the Cancer Prevention Study II Nutrition Cohort.  They found that regular multivitamin use ten years before enrollment was associated with reduced risk of colorectal cancer. 


Lamson DW, Plaza SM.  The anticancer effects of vitamin K.  Altern Med Rev.  2003 Aug;8(3):303-18.

Vitamin K, an essential nutrient often associated with the clotting cascade, has been the focus of considerable research demonstrating an anticancer potential.  Much of this research has focused on vitamin K3, although vitamins K2 and K1 have also been shown to have anticancer effects.  Early studies of vitamin K3 employed an oxidative model to explain the anticancer effects seen in both in vitro and in vivo studies; however, this model does not adequately address the action of vitamins K1 and K2. Recent research has demonstrated the anticancer action of vitamin K may act at the level of tyrosine kinases and phosphatases, modulating various transcription factors such as Myc and Fos, which can lead to cell cycle arrest and cell death.


Montgomery SA, Thal LJ, Amrein R.  Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease.  Int. Clin Psychopharmacol.  2003;18:61-71.

Alcar is a drug currently under investigation for Alzheimer Disease therapy.  Alcar seems to exert a number of central nervous system related effects.  In this study the efficacy of Alcar in mild cognitive impairment was investigated.  The beneficial effects were seen on both the clinical scales and the psychometric tests, within three months and they increased over time.


Shibayama-Imazu T, Sakairi S, Watanabe A, Aiuchi T, Nakajo S, Nakaya K.  Vitamin K(2) selectively induced apoptosis in ovarian TYU-nu and pancreatic MIA PaCa-2 cells out of eight solid tumor cell lines through a mechanism different from geranylgeraniol.  J Cancer Res Clin Oncol.  2003 Jan;129(1):1-11. 

In this study, they examined the effects of MK4 versus geranylgeraniol on various lines from cancer cells derived from solid tumors.  Vitamin 2 induced apoptosis selectively in pancreatic and ovarian cancer cells, and it was suggested that geranylgeraniol (GGO) and MK4 induce apoptosis by different mechanisms.


Tabb MM, Sun A, Zhou C, Grun F, Errandi J, Romero K, et al.  Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR.  J Biol Chem.  2003 Nov 7:278(45):43919-27.

Vitamin K2 is a critical nutrient required for blood clotting that also plays an important role in bone formation.  Vitamin K2 supplementation up-regulates the expression of bone markers, increases bone density and is used clinically in the management of osteoporosis.  Vitamin K2 also activates the expression of the SXR gene, which functions as a therapeutic agent for osteoporosis. 


Yoshida T, Miyazawa K, Kasuga I, Yokoyama T, Minemura K, Ustumi K, et al.  Apoptosis induction of vitamin K2 in lung carcinoma cell lines:  the possibility of vitamin K2 therapy for lung cancer.  Int J Oncol.  2003 Sep;23(3):627-32.

The clinical benefits of using VK2 have been demonstrated for the treatment of the patients with leukemia.  This study examined the in vitro effects of VK2 on lung carcinoma cell lines.  They found that treatment with VK2 results in cell growth suppression in a dose dependent manner in all cell lines tested.  Since VK2 is a safe medicine without prominent adverse effects, their data strongly suggest the therapeutic possibility of using VK2 for the treatment of patients with lung carcinoma. 


Bernker KL, Runge KW.  The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis.  J Thromb Haemost.  2004 Dec;2(12):2118-32.

Recent advances in the discovery of new functions for vitamin K-dependent proteins and in defining vitamin K nutriture have led to a substantial revision in our understanding of vitamin K physiology.  The only unequivocal function for vitamin K is as a cofactor for the caboxylation of Vitamin K dependent proteins which renders them active.  Vitamin K dependent proteins are now known to be present in virtually every tissue and to be important in apoptosis, phagocytosis, cell growth control, chemotaxis, and signal transduction.  New research has revealed that the current recommended daily allowance is insufficient.


Braam L, McKeown N, Jacques P, Lichtenstein A, Vermeer C, Wilson P, et al.  Dietary phylloquinone intake as a potential  marker for a heart-healthy dietary pattern in the Framingham Offspring cohort.  J Am Diet Assoc.  2004 Sep;104(9):1410-4. 

Self reported dietary intakes of phylloquinone (vitamin K1), were evaluated with lifestyle characteristics and markers of cardiovascular disease in a cohort of men and women.  Those in the highest quintile category of phylloquinone intake consumed more fruit, vegetables, fish, dietary fiber, and dietary supplements, and consumed less meat and less saturated fat.  High phylloquinone intakes were also associated with lower triglyceride concentration, making it a marker for overall heart-healthy dietary pattern.


Habu D, Shiomi S, Tamori A, et al.  Role of vitamin K2 in the development of hepatocellular carcinoma in women with viral cirrhosis of the liver.  JAMA. 2004;292(3):358-361.

They studied VK2 in 40 women with viral liver cirrhosis, (HCC), randomly assigned to a treatment or control group.  Originally planned to study the long term effects of VK2 on bone loss in women with cirrhosis.  The treatment group received 45 mg/d of VK2.  There were 21 women in the treatment group and 19 women in the control group.  Only 2 of the 21 who received VK2 got HCC.  9 of the 9 in the control group, who did not receive VK2 got HCC.  The risk for developing HCC in patients with VK2 was .13  They concluded there was a role for VK2 in the prevention of HCC in women with viral cirrhosis. 


Hercberg S, Galan P, Preziosi P, Bertrais S, Mennen L, Malvy D, et al.  The SU.VI.MAX study:  a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals.  Arch Intern Med.  2004 Nov 22;164(21):2335-42. 

In this study they tested the efficacy of nutritional doses of supplementation with a combination of antioxidant vitamins and minerals in reducing the incidence of cancer and ischemic cardiovascular disease in the general population.  They found a significant interaction between sex and group effects on cancer incidence, in that antioxidants had a protective effect in men but not in women.  After 7.5 years, low dose antioxidant supplementation lowered total cancer incidence and all cause mortality in men but not in women. 


International Agency for Research on Cancer.  IARC Monographs on Tobacco Smoking.  Vol 100E. Lyon, France:  IARC:2004; Acrylonitrile; p.43-211.  [cited 2014 May 20].  Available from http://monographs.iarc.fr/ENG/Monographs/vol100E/mono100E-6.pdf


Kato H, Nakamura M, Muramatsu M, Orito E, Ueda R, Mizokami M.  Spontaneous regression of hepatocellular carcinoma:  two case reports and a literature review.  Hepatol Res.  2004 Jul;29(3):180-90. 

Spontaneous regression of a malignant tumor is extremely rare.  This report describes two cases of spontaneous regression of hepatocellular carcinoma (HCC).  Case 1 was a 77 year old male with HCC in the right lobe and multiple lung metastases.  He and his family refused further treatment and he was discharged.  Four months after the diagnosis, dramatic diminution of HCC and lung metastases was noted, and the HCC had disappeared completely 12 months later.  Case 2 was a 72 year old male with multiple nodular regions in the right lobe.  He tested positive for hepatitis C virus.  He and his family refused further treatment and he was followed-up as an outpatient by the local clinic.  Two years later, radiological investigations revealed remarkable regression of the HCC.  Lab analysis showed that PIVKA-II had decreased to the normal range. 


Koike Y, Shiratori Y, Shiina S, et al.  Randomized prospective study of prevention from tumor invasion into portal vein in 120 patients with hepatocellular carcinoma by vitamin K-II.  Gastroenterology.  2002;122:643a.


Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H.  A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer.  N Engl J Med.  2004;350:1200-10.


Otsuka M, Kato N, Shao Rx, Hoshida Y, Ljichi H, Koike Y, et al.  Vitamin K2 inhibits the growth and invasiveness of hepatocellular carcinoma cells via protein kinase A activation.  Hepatology.  2004 Jul;49(1):243-51.

Hepatocellular carcinoma or HCC is a common human malignancy.  Its high mortality rate is the result of high recurrence and portal venous invasion.  Portal vein invasion is related to DCP, which is produced when vitamin K is deficient.  So they explored the link between supplementing with VK2 in HCC cells in vitro and in vivo.  The VK2 effectively reduced both tumor growth and body weight loss. 


Oztopcu P, Kabadere S, Mercangoz A, Uyar R.  Comparison of vitamins K1, K2 and K3 effects on growth of rat glioma and human gliblastoma multiforme cells in vitro.  Acta Neurol Belg.  2004 Sep;104(3):106-10.

Glioblastoma is a highly invasive and rapidly growing cancer.  In this study they exposed the glioma cells to vitamins K1, K2 and K3.  Vitamin K1 showed no growth effect, vitamin K2 did induce growth inhibition, as did vitamin K3.  They concluded that vitamin K3 is more effective than vitamin K2 for inhibition of cancer cell growth, and might serve as an anticancer drug.


Vermeer C, Hamulyak K.  Vitamin K:  lessons from the past.  J Thromb Haemost.  2004 Dec;2(12):2115-7.

Since the 1930s it was believed that blood coagulation was the only process regulated by vitamin K.  Since then we have learned that vitamin K activates a complex enzyme system which is necessary for the functioning of many other proteins, other than blood clotting.  Discovering the first Gla-containing protein, also known as osteocalcin was a milestone in changing our concepts.  Gla-proteins turned out to function as key regulators of important physiological processes including blood coagulation, soft tissue calcification, bone formation, cell growth and apoptosis.  Knowledge from the human genome has led to the identification of two new families of Gla-containing proteins of unknown function, PRGPs and TMGPs.   New evidence has revealed that available protection by vitamin K against cardiovascular calcification is suboptimal in most of the population and that such protection can be improved by simple dietary measures, i.e. vitamin K intake. 


Ames BN.  Increasing longevity by tuning up metabolism.  EMBO Rep.  2005 July; 6(Suppl 1):  S20-S24. 

To maximize human health and lifespan, scientists must abandon outdated models of micronutrients.   Evidence suggests that much chronic metabolic damage occurs from levels of micronutrients that are insufficient to prevent subtle long-term, metabolic damage, with profound repercussions for a large number of other body systems.  The results are an increase in DNA damage, cancer, neuron decay, cognitive dysfunction, or mitrochondrial decay, and accelerated aging and degenerative diseases.  Additionally, optimum amounts of micronutrients varies with age and constitution and genetic makeup, meaning that the requirements of the elderly for vitamins and metabolites are likely to be different from those of the young. 


Erkkila AJ, Booth SL, Hu FB, Jacques PF, Lichtenstein AH.  Phylloquinone intake and risk of cardiovascular diseases in men.  Nutri, Metabol  Cardiov Dis.  2005 Jan;17(1):58-62.

Fong LY, Zhang L, Jiang Y, Farber JL.  Dietary Zinc modulation of COX-2 expression and lingual and esophageal carcinogenesis in rats.  J Natl Cancer Insti.  2005;97: 40-50. 

Cancer of the upper digestive tract, including esophageal and tongue carcinomas, is a major cause of cancer deaths worldwide.  Esophageal and tongue cancers have both been associated with dietary zinc deficiency and cyclooxygenase (COX-2), which is often overexpressed in these cancers.  In this study, they compared zinc deficient and zinc sufficient rats who were treated with a carcinogen.  They found increased cell proliferation in the zinc deficient rats, which facilitated the development of tumors at multiple sites, highlighting risks from nutritional deficiency. 


Hitomi M, Yokoyama F, Kita Y (2005) Antitumor effects of vitamin K1, K2 and K3 on hepatocellular carcinoma in vitro and in vivo.  Int J Oncol 26:713–720.

A number of studies have shown that various K vitamins, specifically vitamins K2 and K3, possess antitumor activity on cancer cell lines.  In this study, they examined the antitumor effects of vitamins K1, K2 and K3 on PLC/PRF/5 human hepatocellular carcinoma (HCC) cells in vitro and in vivo, and the mechanisms of those antitumor actions.  Although vitamin K1 did not inhibit proliferation of PLC/PRF/5 cells at a 90-microM concentration (the highest tested), vitamins K2 and K3 suppressed proliferation of the cells at concentrations of 90 and 9 microM, respectively . Taken collectively, vitamins K2 and K3 were able to induce potent antitumor effects on HCC in vitro and in vivo, at least in part, by inducing G1 arrest of the cell cycle. The results indicate that vitamins K2 and K3 may be useful agents for the treatment of patients with HCC.


Iguchi T, Miyazawa K, Asada M, Gotoh A, Mizutani S, Ohyashiki K.  Combined treatment of leukemia cells with vitamin K2 and 1alpha,25-dihydroxy vitamin D3 enhances monocytic differentiation along with becoming resistant to apoptosis by induction of cytoplasmic p21C1P1.  Int J Oncol.  2005 Oct;27(4):893-900.

Vitamin K2 effectively induces apoptosis in leukemia cell lines.  Combining vitamin K2 with vitamin D3 was also an effective combination for differentiation-based therapy for leukemia.  

Iguchi T, Miyazawa K, Asada M, Gotoh A, Mizutani S, Ohyashiki K.  Combined treatment of leukemia cells with vitamin K2 and 1alpha,25-dihydroxy vitamin D3 enhances monocytic differentiation along with becoming resistant to apoptosis by induction of cytoplasmic p21C1P1. Int J Oncol.  2005 Oct;27(4):893-900.

The combination of vitamin K2 with vitamin D2 achieved good differentiation in a lab study of leukemia cells, suggesting that it might be effective therapy for both MDS and leukemia.  Vitamin K2 effectively induces apoptosis in leukemia cell lines.  Combining vitamin K2 with vitamin D3 was also an effective combination for differentiation-based therapy for leukemia


Kuriyama S, Hitomi M, Yoshiji H, Nonomura T, Tsujimoto T, Mitoro A, et al.  Vitamins K2, K3 and K5 exert in vivo antitumor effects on hepatocellular carcinoma by regulating the expression of G1 phase-related cell cycle molecules.  Int J Oncol.  2005 Aug;27(2):505-11.

A number of studies have shown that various K vitamins, specifically vitamin K2, possess antitumor activity on various types of rodent and human derived cancer cell lines.  The mechanism still remains to be examined.  In this study they examined the antitumor effects of vitamins K2, K3, and K5 on HCC cells in vivo in mice.  The vitamin Ks markedly inhibited the growth of HCC tumors by regulating the expression of G1 cell cycle molecules.


McCann JC, Ames BN.  Is docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid, required for normal brain function?  An overview of evidence from cognitive and behavioral tests in humans and animals:  a review.  Am J Clin Nutr.  2005;82:281-95.


Moshfegh A, Goldman J, Cleveland L.  What we eat in America.  NHANES 2001 2002:  usual nutrient intakes from food compared to dietary reference intakes.  Washington, DC:U.S. Department of Agriculture Agricultural Research Service;  2005. 

The actual intakes of various micronutrients from food are inadequate for the poor, teenagers, menstruating women, the obese, the elderly, and for much of the rest of the population.


Parkin DM, Bray F, Ferlay j, Pisani P.  Global  cancer statistics, 2002:  CA:  A Cancer J for Clin.  2005;55(2):74-108.


Shibuya K, Yano E.  Regression analysis of trends in mortality from hepatocellular carcinoma in Japan, 1972-2001.  Int J Epidemiol.  2005;34:397-402.


Smeenk HG, Tran TC, Erdmann J, van Eijck CH, Jeekel J.  Survival after surgical management of pancreatic adenocarcinoma:  does curative and radical surgery truly exist?  Langenbecks Arch Surg.  2005 Apr;390(2):94-103.

Surgery for pancreatic cancer offers a low success rate, with a 5 year survival rate of 10-20%.  Most patients develop recurrent disease within 2 years after surgery.  Adjuvant therapy has so far shown only modest results.  Long term survival is observed in only a very small group of patients. Other treatment options are needed.


Yokoyama T, Miyazawa K, Yoshida T, Ohyashiki K.  Combination of vitamin K2 plus imatinib mesylate enhances induction of apoptosis in small cell lung cancer cell lines.  Int J Oncol.  2005 Jan;26(1):33-40.

Combined VK2, specifically MK4, with imatinib mesylate, is a growth inhibitor of small cell lung cancer.  Treatment with this combination resulted in a pronounced suppression of cell growth in a dose dependent manner in all cell lines tested.  Since VK2 is a safe medicine without prominent adverse effects, treatment of patients with SCLC could offer therapeutic benefits from this combination.


Yoshiji H, Kuriyama S, Noguchi R, Yoshii J, Ikenaka Y, Yanase K, et al.   Combination of vitamin K2 and the angiotensin-converting enzyme inhibitor, perindopril, attentuates the liver enzyme-altered preneoplastic lesions in rats via angiogenesis suppression.  J Hepatol.  2005 May;42(5):687-92.

Angiogenesis, which is the creation of a blood supply, is now recognized as a crucial step in early carcinogenesis.  This study looked at the combination effect of VK2 and enzyme inhibitor Perindopril on hepatocarcinogenesis.  Treatment with both markedly inhibited the development of lesions and suppressed the lesions spreading in the liver.  The combination treatment was more potent then single agent treatment.  This combo therapy may represent a potential new strategy for chemoprevention against HCC in the future.


Ames BN.  Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scare micronutrients by triage.  Proc Natl Acad Sci USA.  2006 Nov 21;103(47):17589-94. 

Inadequate dietary intake of vitamins and minerals are widespread, likely due to excessive consumption of energy-rich, micronutrient-poor, refined food.  Inadequate intakes may result in chronic metabolic disruption, including mitochondrial decay.  Deficiencies in many micronutrients cause DNA damage, such as chromosome breaks.  Some of these deficiencies also cause mitochondrial decay with cellular aging and are associated with late onset diseases such as cancer. The authors propose that DNA damage and late onset disease are consequences of a triage allocation response to micronutrient scarcity.  Episodic shortages of micronutrients were common during evolution. Natural selection favors short-term survival at the expense of long-term health. I hypothesize that short-term survival was achieved by allocating scarce micronutrients by triage.  If this hypothesis is correct, micronutrient deficiencies that trigger the triage response would accelerate cancer, aging, and neural decay but would leave critical metabolic functions, such as ATP production, intact.  There is evidence that micronutrient malnutrition increases late onset diseases, such as cancer.  Taking vitamin supplements is a low cost way to ensure adequate intake of the Recommended Dietary Allowance of micronutrients throughout life.


Bartsch H, Nair J.  Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer:  role of lipid peroxidation, DNA damage, and repair.  Langenbecks Arch Surg.  2006 sep;391(4):499-510. 

Persistent oxidative stress and excess lipid peroxidation are induced by inflammatory processes in a self-perpetuating process and cause progressive accumulation of DNA damage in target organs.  The resulting genetic changes act as driving force in chronic inflammation associated disease. 


Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL.  Vitamin K contents of meat, dairy and fast foods in the US diet.  J Agric Food Chem.  2006;54:463-67.

This study determined the contents of three forms of vitamin K in samples of meat, dairy, eggs, and fast foods common to the U.S. diet.  The findings showed that no single food item in these categories is a rich dietary source of any one form of vitamin K. 


Heaney RP.  Nutrition and chronic disease.  Mayo Clin Proc.  2006 Mar;81(3):297-9.

The first victories of human clinical nutrition were the conquests of the classic deficiency diseases (eg. Beri-beri and pellagra).  Each nutrient was associated with a specific disease, the mechanism of its action was elucidated and programs of supplementation led to control or virtual elimination of the disease.  Most of this occurred more than half a century ago, and with those gains to its credit, nutrition has virtually disappeared from the radar screens of many medical specialties.  Going forward, clinical nutrition science needs to develop investigative approaches to define the role that nutritional deficiency plays in a broad array of chronic diseases, showing efficacy in a context of long latency,  and also address the fact that American medicine ignores or dismisses nutritional evidence relating to the diseases it treats.


Jung B, Ahmad N.  Melatonin in cancer management:  progress and promise.  Cancer Res.  2006 Oct 15;66(20):9789-93.

The hormone melatonin has shown anti cancer effects in a variety of in vitro and in vivo experimental models of cancer.  Multiple mechanisms have been suggested.  Additionally it has the potential to increase the efficacy and decrease the side effects of chemotherapy.  This review evaluates the progress of melatonin to prevent or reverse cancer development and progression.


Mancuso A, Calabro F, Sternberg CN.  Current therapies and advances in the treatment of pancreatic cancer.  Crit Rev Oncol Hematol.  2006 Jun;58(3):231-41.

Pancreatic cancer is a common, highly lethal disease with a rising incidence.  In recent years, new biological treatment agents may show promise. 


Matsumoto K, Okano J, Nagahara T, Murawaki Y.  Apoptosis of liver cancer cells by vitamin K2 and enhancement by MEK inhibition.  Int J Oncol.  2006 Dec;29(6):1501-8.

Vitamin K2 is an anti-proliferative agent toward a variety of cancers including hepatocellular carcinoma (HCC).  This study investigated the growth inhibitory effect of VK2 on HCC cells in vitro.  VK2 inhibited the growth of Hep3B but not three others.  The data demonstrated that VK2 induced apoptosis. 


Mizuta T, Ozaki I, Eguchi Y, Yasutake T, Kawazoe S, Fujimoto K, et al. The effect of menatetrenone, a vitamin K2 analog, on disease recurrence and survival in patients with hepatocellular carcinoma after curative treatment. Cancer 2006; 106: 867-872.

The high recurrence rate of hepatocellular carcinoma (HCC) determines the long-term prognosis for patients with HCC.  This study tested the effects of MK4 on recurrent HCC and survival after curative treatment.  64 patients were assigned to a control group or a treatment group, whom received 45 mg of MK4 daily.  Analysis showed that the MK4 was the only factor related to the recurrence rate.  They concluded that MK4 may have a suppressive effect on cancer recurrence and a beneficial effect on long-term survival


Neogi T, Booth SL, Zhang YQ, Jacques PF, Terkeltaub R, Aliabadi P, et al.  Low vitamin K status is associated with osteoarthritis in the hand and knee.  Arthritis Rheum.  2006apr;54(4):1255-61.


Shibayama-Imazu T, Sonoda I, Sakairi S, Aiuchi T, Ann WW, Nakajo S, et al.  Production of superoxide and dissipation of mitochondrial transmembrane potential by vitamin K2 trigger apoptosis in human ovarian cancer TYK-nu cells.  Apoptosis.  2006 Sep;11(9):1535-43.


Tokita H, Tsuchida A, Miyazawa K, Ohyashiki K, Katayanagi S, Sudo H, et al.  Vitamin K2-induced antitumor effects via cell-cycle arrest and apoptosis in gastric cancer cell lines.  Int J Mol Med.  2006 Feb;17(2):235-43.

In this study, the effect of VK2, specifically MK4, on gastric cancer cell lines were examined.  When 4 kinds of gastric cancer cells were exposed to MK4, the cell growth was inhibited in a dose dependent manner.   MK4 was also combined with other anticancer agents, and alone or combined, MK4 had an antitumor effect on gastric cancer cell lines. 


Tsujioka T, Miura Y, Otsuki T, Nishimura Y, Hyodoh F, Wada H.  The mechanisms of vitamin K2-induced apoptosis of myeloma cells.  Haematologica.  2006;91:613-19.

Treated myeloma, lymphoma and non-lymphoid cancer cells with various concentrations of VK2 with or without demamethasone or allopurinol, which are agents used to treat side effects.  Myeloma and B-cell Lymphoma cells were sensitive to VK2, indicating that VK2 could be a viable treatment.


Brunetti-Pierri N, Hunter JV, Boerkoel CF.  Gray matter heterotopias and brachytelephalangic chondrodysplasia punctata: a complication of hyperemesis gravidarum induced vitamin K deficiency?  Am J Med Genet A.  2007 Jan 15;143(2):200-4.


Cranenburg ECM, Schurgers LJ, Vermeer C.  Vitamin K:  The coagulation vitamin that became omnipotent.  Thomb Haemost.  2007;98:120-125.

Vitamin K was discovered in the 1930s.  Research has indicated that the majority of people have a subclinical deficiency in vitamin K, meaning the biological activity of these proteins is sub-optimal.  Research suggests that although dietary vitamin K intake is adequate to maintain normal haemostasis, it may be insufficient for extrahepatic tissues.  Poor vitamin K status must be regarded as a serious risk factor for bone loss, artery calcification, diabetes, kidney disease, and aging.   Supplementing with vitamin K as well as increasing its dietary intake could improve human health.


Enomoto M, Tsuchida A, Miyazawa K, et al. Vitamin K2-induced cell growth inhibition via autophagy formation in cholangiocellular carcinoma cell lines. Int J Mol Med. 2007 Dec;20(6):801-8.


Erkkila AT, Booth SL, Hu FB, Jacques PF, Lichtenstein AH.  Phylloquinone intake and risk of cardiovascular diseases in men.  Nutri Metab Cardiovasc Dis.  2007 Jan;17(1):58-62.

Hoang BX, Shaw DG, Pham PT, Levine SA.  Neurobiological effects of melatonin as related to cancer.  Eur J Cancer Prev.  2007 Dec;16(6):511-6.

Melatonin is a neurohormone naturally found in humans, and it plays a role in maintaining sleep-wake rhythms.  It may have a compelling role in the treatment of cancer.  High levels of melatonin have been linked to slower cancer progression, though the mechanism remains unclear.  In this study they try to elucidate the anticancer effects of melatonin.


Holden RM, Booth SL.  Vascular calcification in chronic kidney disease:  the role of vitamin K.  Nat Clin Pract Nephrel.  2007 Oct;3(10):522-3.


Hotta N, Ayada M, Sato K, Ishikawa T, Okumura A, Matsumoto E, et al.  Effect of vitamin K2 on the recurrence in patients with hepatocellular carcinoma.  Hepatogastroenterology.  2007 Oct-Nov;54(79):2073-7.

Kanamori T, Shimizu M, Okuno M, Matsushima-Nishiwaki R, Tsurumi H, Kojima S, et al.  Synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells.  Cancer Science.  2007 March;98(3):431-37.

HCC is one of the most prevalent cancers worldwide.  However effective chemopreventive and chemotherapeutic agents for this cancer have not yet been developed.  In clinical trials, acylic retinoid (ACR) and vitamin K2 decreased the recurrence rate of HCC.  In this study they looked at the combined effects of ACR plus VK2 in a human HCC cell line, and found that they synergistically inhibited the growth of huH7 cells without affecting normal cells.  These results suggest that retinoids, especially ACR and VK2 cooperatively inhibit the growth of HCC cells, and therefore might be effective for chemoprevention and chemotherapy


Kakizaki S, Sohara N, Sato K, Suzuki H, Yanagisawa M, Nakajima H, et al.  Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection.  J Gastroenterol Hepatol.  2007 Apr;22(4):518-22.

Found that vitamin K2 had a suppressive effect on the recurrence of HCC and a beneficial effect on tumor recurrence.  However, they found no significant difference in the survival rates.  The authors encourage exploration of combination therapy, using vitamin K2 with other agents.


Knapen MH, Schurgers LJ, Vermeer C.  Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women.  Osteoporos Int.  2007 Jul;18(7):963-72.

Vitamin K2 helps bone strength at the site of the femoral neck in postmenopausal women by improving BMC and FNW, whereas it has little effect on DXA-BMD.


Lin WW, Karin M.  A cytokine-mediated link between innate immunity, inflammation, and cancer.  J Clin Invest.  2007 May;117(5):1175-83.

It is well established that cancer can be promoted by inflammation and infections.  Chronic inflammation orchestrates a tumor-supporting microenvironment that is indispensable in the new cancer process. 


Liu W, Nakamura H, Yamamoto T, Ikeda N, Saito M, Ohno M, et al.  Vitamin K2 inhibits the proliferation of HepG2 cells by up-regulating the transcription of p21 gene.  Hepatol Res.  2007 May;37(5):360-5.


McCann J, Hudes M, Ames BN.  An overview of evidence for a causal relationship between dietary availability of choline during development and cognitive function in offspring.  Neurosci and Biobehav Revs.  2006;30:696-712.

This review is part of a series intended for non-specialists that provides an overview of evidence for causal relationships between micronutrient deficiencies and brain function.  The evidence in the literature suggests that choline supplementation during development results in improved performance of offspring in cognitive or behavioral tests and results in changes in a variety of neurological functional indicators, such as enhanced performance on difficult tasks, and protection against the adverse effects of neurotoxic agents.


Mizuta T, Ozaki I.  Clinical application of vitamin K for hepatocellular carcinoma.  Clin Calcium.  2007 Nov;17(11):1693-9. 

Despite recent progress in diagnosis and therapy, HCC remains among the cancers with the poorest prognoses.  Vitamin K has been shown to suppress growth of HCC cells.  Long term administration of VK2 has established its clinical safety, but it does not appear to exhibit marked anti-tumor effects when administered alone.  For more effective use of VK against HCC, co-administration of VK2 with other proven anticancer agents should be investigated in the future.


Oettle H, Neuhaus P.  Adjuvant therapy in pancreatic cancer:  a critical appraisal.  Drugs.  2007;67(16):2293-310.

Pancreatic cancer carries a grim prognosis.  Surgery is the only curative option, but patients run a high risk for relapse and death.  Although numerous clinical trials have been conducted during the past 20 years to find an effective treatment, there is no consensus on the most appropriate regimen.  Available data suggest that chemoradiotherapy has no advantage, and that chemotherapy with gemcitabine is the best benefit-risk ration of all currently adjuvant treatment options.


Ogawa M, Nakai S, Deguchi A, Nonomura T, Masaki T, Uchida N, Yoshiji H, Kuriyama S.  Vitamins K2, K3, and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells.  Int J Oncol.  2007 Aug;31(2):323-31.

The antitumor effects of vitamin K on colorectal cancer were examined both in vitro and in vivo.  The results indicated that the IV administration of vitamins K2, K3 and K5 significantly suppressed the tumor growth in vivo and in vitro by inducing apoptotic death, suggesting that these K vitamins may be promising agents for the treatment of patients with CRC


Ozaki I, Zhang H, Mizuta T, Ide Y, Eguchi Y, Yasutake T, et al.  Menatetrenone, a vitamin K2 analogue, inhibits hepatocellular carcinoma cell growth by suppressing Cyclin D1 expression through inhibiton of nuclear factor kappaB activation.  Clin Cancer Res.  2007 Apr;13:2236. 

Menatetrenone (Mk4) has been shown to have anti cancer effects against several cancer cell lines including HCC cells.  However the mechanisms have not been fully clarified.  In this study HCC cells were treated with vitamin K2 and the expression of several growth related genes were examined.  The results showed that vitamin K2 inhibited the growth of HCCcells via gene suppression and might be useful as a treatment agent.


Pearson DA.  Bone health and osteoporosis:  the role of vitamin K and potential antagonism by anticoagulants.  Nutr Clin Pract.  2007 Oct;22(5):517-44.


Pilkey RM, Morton AR, Boffa MB, Noordhof C, Day AG, Su Y, et al.  Subclinical vitamin K deficiency in hemodialysis patients.  Am J Kidney Dis.  2007 Mar;49(3):432-9.


Schurgers LJ, Spronk HM, Skepper JN, Hackeng TM, Shanahan CM, Vermeer C, et al.  Post-translational modifications regulate matrix Gla protein function:  importance for inhibition of vascular smooth muscle cell calcification.  J Thromb Haemost.  2007 Dec;5(12):2503-11.


Schurgers LJ, Teunissen KJ, Hamulyak K, Knapen MH, Vik H, Vermeer C.  Vitamin K-containing dietary supplements:  comparison of synthetic vitamin K1 and natto-derived menaquinone-7.  Blood.  2007 Apr 15;109(8):3279-83.

Accumulating evidence suggests that relatively high intakes of vitamin K are required for optimal bone and vascular health.   The synthetic short-chain vitamin K1 is commonly used in food supplements, but recently the natural long-chain menaquinone (MK7) has also become available as an over the counter supplement.  In this study they compared the absorption and efficacy of K1 and MK4 in healthy volunteers.  Both were absorbed well, with peak serum concentrations at 4 hours after intake.  A major difference was the very long half-life time of MK7, resulting in much more stable serum levels and accumulation of MK7 to higher levels (7-8 times fold) during prolonged intake.  MK7 induced more complete carboxylation of osteocalcin.


Tamori A, Habu D, Shiomi S, Kubo S, Nishiguchi S.  Potential role of vitamin K2 as a chemopreventive agent against hepatocellular carcinoma.  Hepatology.  2007;37(s2):S303-S307.

In hepatoma cells, vitamin K2 causes cell-cycle arrest and apoptosis.  The safety, relatively low cost , and ease of use of vitamin K2 have led to good compliance with treatment.  The results of preliminary clinical trials are intriguing and suggest that vitamin K2 might reduce the risk of HCC in patients with liver cirrhosis as well as prevent disease recurrence after curative therapy.


Bugel S.  Vitamin K and bone health in adult humans.  Vitam Horm.  2008;78:393-416.

Vitamin K insufficiency is associated with low bone mineral density, and increased fractures. 


Cashman KD, O’Connor E.  Does high vitamin K1 intake protect against bone loss in later life?  Nutr Rev.  2008 Sep;66(9):532-8.


Coutu DL, Wu JH, Monette A, Rivard GE, Blostein MD, Galipeau J.  Periostin, a member of a novel family of vitamin K-dependent proteins, is expressed by mesenchymal stromal cells.  J Biol Chem.  2008 Jun 27;283(26):17991-8001.


Danziger J.  The bone-renal axis in early chronic kidney disease:  an emerging paradigm.  Nephrol Dial Transplant.  2008;23(9):2733-37.


Erkkila AT, Booth SL.  Vitamin K intake and atherosclerosis.  Curr Opin Lipidol.  2008 Feb;19(1):39-42.


Heiss C, Hoesel LM, Wehr U, Wenisch S, Drosse I, Alt V, et al.  Diagnosis of osteoporosis with vitamin K as a new biochemical marker.  Vitam Horm.  2008;78:417-34.

Osteporosis is a metabolic bone disease characterized by reduced bone quality and quantity.   As a consequence, patients are at risk for fractures, subsequent immobility, and higher mortality, especially among elder patients.  Because of the high incidence of complications and the associated financial burden for the healthy system, new parameters for diagnostic and therapeutic purposes are urgently needed.  Research is focused on vitamin K as a biochemical bone marker, and the results are promising.


Ishimura E, Okuno S, Taniwaki H, Kizu A, Tsuchida T, Shioi A, et al.  Different risk factors for vascular calcification in end-stage renal disease between diabetics and nondiabetics:  the respective importance of glycemic and phosphate control.  Kidney Blood Press Res.  2008;31(1):10-5.


Kaneda M, Zhang D, Bhattacharjee R, Nakahama K, Arii S, Morita I.  Vitamin K2 suppresses malignancy of HuH7 hepatoma cells via inhibition of connexin 43.  Cancer Lett.  2008 May 8:263(1):53-60.

The anticancer potential of vitamin K2 in hepatoma has gained considerable attention but the underlying mechanisms are unclear.  Treatment of HuH7 hepatoma cells with VK2 produced a normal liver phenotype.  They propose that the anti-tumor effect of VK2 is partly due to a decrease in Cx43 activity.


McCann JC, Ames BN.  Review article:  is there convincing biological or behavioral evidence linking vitamin D deficiency to brain dysfunction?  FASEB J.  2008;22:982-1001.

Vitamin D insufficiency is common in the USA; particularly with the elderly and African-Americans.  This review concludes that there is ample biological evidence to suggest an important role for vitamin D in brain development and function.  However, direct effects of vitamin D inadequacy appear to be subtle.  Recommendations for vitamin D supplementation for at-risk groups appear warranted. 


Nimptsch K, Rohrmann S, Linseisen J.  Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition ( EPIC-Heidelberg).  Am J Clin Nutr.  2008 Apr;87(4):985-92.

Anticarcinogenic activities of vitamin K have been observed in various cancer cell lines, including prostate cancer cells.  In this study, they evaluated the association between dietary intake of phylloquinone and menaquinones and total and advanced prostate cancer in the Heidelberg cohort.  The results suggest an inverse association between the intake of menaquinones, but not that of phylloquinone and prostate cancer, meaning that the more menaquinones you take in, the lower the risk of prostate cancer.


Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, et al.  Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma:  a randomized controlled trial.  JAMA.  2008 Mar 5;299(9):1019-26.


Sakagami H, Hashimoto K, Suzuki F, Ishihara M, Kikuchi H, Katayama T, et al.  Tumoro-specificity and type of cell death induced by vitamin K2 derivates and prenylalcohols.  Anticancer Res.  2008 Jan-Feb;28(1A):151-8.

Fourteen vitamin K2 (MK1-15) and ten prenylalcohol derivatives were investigated for their cytotoxicity against nine human tumor cell lines and three human normal oral cells.  MK2 showed the greatest cytotoxicity followed by MK1 and MK3.  The human leukemia cell lines were the most sensitive


Schurgers LJ, Cranenburg EC, Vermeer C.  Matrix Gla-protein:  the calcification inhibitor in need of vitamin K.  Thromb Haemost.  2008 Oct;100(4):593-603. 

Among the proteins involved in vascular calcium metabolism, the vitamin K dependent matrix Gla-protein (MGP) plays a dominant role.  Although on a molecular level its mechanism of action is not completely understood, it is generally accepted that MGP is a potent inhibitor of arterial calcification.  The optimal vitamin K intake is therefore important to maintain the risk and rate of calcification as low as possible. 


Shea MK, Booth SL.  Update on the role of vitamin K in skeletal health.  Nutr Rev.  2008 Oct;66(10):549-57.


Shearer MJ, Newman P.  Metabolism and cell biology of vitamin K.  Thromb Haemost.  2008;100:530-47.

The structural differences in the isoprenoid side chain of the chemical structures of the different vitamin Ks are important in vitamin K metabolism, including they way they are transported, taken up by target tissues, and subsequently excreted.  Phylloquinone is transported mainly by triglyceride rich lipoproteins and long chain menaquinones are transported mainly by low density lipoproteins (LDL).  TRL borne phylloquinone uptake by osteoblasts is an ApoE mediated process with the LRP1 receptor playing a predominant role.  MK4, has a highly specific tissue distribution suggestive of local synthesis from phylloquinone. Both MK4 and phylloquinone activate the steroid and xenobiotic receptor (SCR).  Many studies have shown specific clinical benefits of MK4 at pharmacological doses for osteoporosis and cancer although the mechanisms are poorly understood.  Other functions of vitamin K include the suppression of inflammation, prevention of brain oxidative damage and a role in sphingolipid synthesis.  In humans, MK7 has a greater efficacy than phylloquinone in carboxylating both liver and bone gla proteins. 


Shibayama-Imazu T, Aiuchi T, Nakaya K.  Vitamin K2-mediated apoptosis in cancer cells:  role of mitochondrial transmembrane potential.  Vitam Horm.  2008;78:211-26.

Vitamin K2 induces differentiation and apoptosis in a wide array of human cancer cell lines.  Vitamin K2-mediated apoptosis proceeds much more slowly than the apoptosis induced by conventional anticancer agents.  Ovarian cancer cells were treated with vitamin K2, and the data suggest that apoptotic features are visible within four days. 


Shibayama-Imazu T, Fujisawa Y, Masuda Y, Aiuchi T, Nakajo S, Itabe H, et al.  Induction of apoptosis in Pa-1ovarian cancer cells by vitamin K2 is associated with an increase in the level of TR3/Nur77 and its accumulation in mitochondria and nuclei.  J Cancer Res Clin Oncol.  2008;134:803-12.


Yokoyama T, Miyazawa K, Naito M, Toyotake J, Tauchi T, Itoh M, et al.  Vitamin K2 induces autophagy and apoptosis simultaneously in leukemia cells.  Autophagy.  2008 July 1;4(5):629-640.

Vitamin K2 (MK4) is a potent inducer for apoptosis in leukemia cells in vitro.  This study indicates that VK2 can simultaneously induce both autophagy and apoptosis.  Apoptosis is an orchestrated cell death process which does not elicit an inflammatory response.  Many anti-cancer agents and treatments are mediated through apoptosis of cancer cells.  Autophagy also leads to cell death through different mechanisms.


Yoshida M, Booth SL, Meigs JB, Saltzman E, Jacques PF.  Phylloquinone intake, insulin sensitivity, and glycemic status in men and women.  Am J Clin Nutr.  2008 Jul;88(1):210-5.

They examined the associations between vitamin K intake and measures of insulin sensitivity and glycemic status in men and women, aged 26-81 years.  They found that high phylloquinone intake was associated with greater insulin sensitivity and glycemic status, supporting a potential beneficial role for phylloquinone in glucose homeostasis in men and women.


Yoshida M, Jacques PF, Meigs JB, Saltzman E, Shea MK, Gundberg C, et al.  Effect of vitamin K supplementation on insulin resistance in older men and women.  Diabetes Care.  2008 Nov;31(11):2092-6.

They tested the hypothesis that vitamin K supplementation for 36 months will improve insulin resistance in older men and women.  Administered 500 microg/day phylloquinone for 36 months to nondiabetic men and women, aged 60-80 years.  Insulin resistance was significantly lower in men who had received vitamin K, but not in the women.  They concluded that vitamin K supplements for 36 months may reduce the progression of insulin resistance in older men.

 

Ames BN, McCann JM.  Foreward:  Prevention of cancer, and the other degenerative diseases of aging, through nutrition.  In: Knasmuller S, DeMarini DM, Johnson I, Gerhauser C, editors.  Chemoprevention of cancer and DNA damage by dietary factors.  KGaA, Germany:  Wiley-VCH Verlag GmbH & Co.  2009.  Xxxi-xxxviii. 

The many degenerative diseases accompanying aging, such as cancer, immune dysfunction, cognitive decline, cardiovascular disease, and stroke, might be delayed by an inexpensive intervention. Triage Theory posits that when a micronutrient is inadequate, nature selects for a rebalancing of metabolism, that ensures survival of the organism at the expense of less critical metabolism, and the consequences of this rebalancing include the chronic diseases of aging.  The Triage Theory predicts that optimizing intake of approximately 40 essential micronutrients will reduce the risk of chronic diseases associated with aging and increase life span.  Micronutrients are remarkably inexpensive, and intakes below recommended levels are unusually widespread not only in poor countries but also in US population across all segments of society.  They believe that an insidious consequence of micronutrient triage are future cancers, future infections and future brain aging. 


Hirpara KV, Aggarwal P, Mukherjee AJ, Joshi N, Burman AC. Quercetin and its derivaties: synthesis, pharmacological uses with special emphasis on antitumor properties and prodrug with enhanced bio-availability.  Anticancer Agents Med Chem.  2009 Feb;((2):138-61.

Cancer is one of the leading causes of death in the world.  American Cancer Society reported 12 million new cases of malignancy diagnosed worldwide in 2007, with 7.6 million people dying from the disease.  Plant-derived molecules have played an important role in cancer chemotherapy.  Quercetin is emerging as a prospective anticancer drug candidate and is in phase 1 clinical studies. 


Kawakita H, Tsuchida A, Miyazawa K, Nalto M, Shigoka M, Kyo B, et al.  Growth inhibitory effects of vitamin K2 on colon cancer lines via different types of cell death including autophagy and apoptosis.  Int J Mol Med.  2009;23:709-16.

Vitamin K2 (MK4) has been reported to inhibit cell growth and induce apoptosis in various tumor cells.  They examined the effects of MK4 using three types of colon cancer cell lines.  The response to MK4 and the induction of cell death varied in different cancer cell lines. 

 

McCann JC, Ames BN.  Vitamin K, an example of triage theory:  is micronutrient inadequacy linked to diseases of aging?  Am J Clin Nutr.  2009 Oct;90(4):889-907. 

Micronutrients are approximately 40 essential vitamins, minerals, fatty acids and amino acids.  The triage theory posits that some functions from these micronutrients are restricted by the body during shortage and the functions required for short-term survival take precedence over those that are less essential. Insidious changes accumulate as a consequence of restriction, which increases the risk of diseases of aging.  We evaluated the relative lethality of 11 known mouse knockout mutants for 16 known vitamin K dependent (VKD) proteins to categorize essentiality.  Results indicated that 5 VKD proteins that are required for coagulation had critical functions and the mice would die as embryos when deprived of them.  Whereas the mice that had the 5 less critical VKD proteins [osteocalcin, matrix Gla protein (Mgp), growth arrest specific protein 6, transforming growth factor beta-inducible protein (Tgfbi or betaig-h3), and periostin] survived at least through weaning.  Genetic loss of less critical VKD proteins, dietary vitamin K inadequacy, human polymorphisms or mutations, and vitamin K deficiency induced by chronic anticoagulant (warfarin/coumadin) therapy are all linked to age-associated conditions: bone fragility after estrogen loss (osteocalcin) and arterial calcification linked to cardiovascular disease (Mgp, and cancer.  A triage perspective reinforces recommendations of some experts that much of the population and warfarin/coumadin patients may not receive sufficient vitamin K for optimal function of VKD proteins that are important to maintain long-term health.


Nimptsch K, Rohrmann S, Nieters A, Linseisen J.  Serum undercarboxylated osteocalcin as biomarker of vitamin K intake and risk of prostate cancer:  a nested case-control study in the Heidelberg cohort of the European prospective investigation into cancer and nutrition.  Cancer Epidemiol Biomarkers Prev.  2009 Jan;18(1):49-56.

Vitamin K is known to exert anticancer effects on a variety of cancer cell lines, including prostate cancer cells.  In this study, they aimed to confirm the cancer-protective effect using serum undercarboxylated osteocalcin (ucOC), a biomarker of vitamin K status inversely associated with vitamin K intake.  They confirmed the significant association between menaquinone intake and advanced stage prostate cancer.  There was also indication of a lower prostate cancer risk in carriers of the A allele.  These results strengthen the hypothesis that vitamin K intake and status plays a role in the etiology of prostate cancer.  


Nowak D, Stewart D, Koeffler HP.  Differentiation therapy of leukemia:  3 decades of development.  Blood.  2009 Apr 16;113(16):3655-65.


Tkatchenko TV, Moreno-Rodriguez RA, Conway SJ, Molkentin JD, Markwald RR, Tkatchenko AV.  Lack of periostin leads to suppression of Notch1 signaling and calcific aortic valve disease.  Physiol Genomics.  2009 Nov 6;39(3):160-8.


Visconti R, Grieco D.  New insights on oxidative stress in cancer.  Curr Opin Drug discov Devel.  2009 Mar;12(2)240-5.


Yamamoto T, Nakamura H, Liu W, Cao K, Yoshikawa S, Enomoto H, et al.  Involvement of hepatoma-derived growth factor in the growth inhibition of hepatocellular carcinoma cells by vitamin K(2).  J Gastroenterol.  2009;44(3):228-35. 

They looked at a growth factor in HCC/liver cancer, HDGF, that is highly expressed in HCC cells and is a possible prognostic factor for patients with HCC.  Three HCC-derived cell lines were used.  They found that VK2 suppressed the growth of three HCC cell lines in a dose dependent manner.  VK2 significantly suppressed the expression of the HDGF protein in three cell lines, interfering with the growth of the cancer cells.  Based on these results it appears that the regulation of HDGF gene expression is one of the crucial mechanisms of VK2 induced cell growth suppression for HCC.


Yamamoto T, Nakamura H, Liu W, Cao K, Yoshikawa S, Enomoto H, et al.  Involvement of hepatoma-derived growth factor in the growth inhibition of hepatocellular carcinoma cells by vitamin K2.  Journal of Gastroenterology.  2009;44(3):228-235.

This study found that VK2 suppressed the growth of three HCC cell lines, and the findings suggest that regulation of HDGF  gene expression is one of the crucial mechanisms of vitamin K2 induced, cell growth suppression of HCC.


Yoshiji H, Noguchi R, Toyohara M, Ikenaka Y, Kitade M, Kaji K, et al.  Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma.  J Hepatol.  2009 Aug;51(2):315-21.

No chemopreventive agent has been approved against HCC yet.  This study aimed to elucidate the combined effect of the clinically used vitamin K2 and ACE-1, the angiotensin-converting enzyme inhibitor on the cumulative recurrence of HCC.  A 48 month follow up revealed that the combination treatment of VK and ACE-I markedly inhibited the cumulative recurrence of HCC.


Zhang Y, Wen G, Shao G, Wang C, Lin C, Fang H, et al.  TGFBI deficiency predisposes mice to spontaneous tumor development.  Cancer Res.  2001 Jan;69:37.

TGFBI is a vitamin K dependent protein.  It has been implicated in cell proliferation, tumor progression and angiogenesis of cancer.  In this study, they generated a mouse model where TGFBI was disrupted.  Mice lacking TGFBI were prone to spontaneous tumors.   They provided the first evidence that TGFBI functions as a tumor suppressor in vivo.  And since TGFBI depends on an adequate supply of vitamin K, it suggests that intake of vitamin K may have a role in cancer.


2010s

Akiyama N, Miyazawa K, Kanda Y, Tohyama K, Omine M, Mitani K, et al.  Multicenter phase II trial of vitamin K(2) monotherapy and vitamin K(2) plus 1alpha-hydroxyvitamin D(3) combination therapy for low-risk myelodysplastic syndromes.  Leuk Res.  2010 Sep;34(9):1151-7.

This study demonstrated that vitamin K2 plus vitamin D3 combination therapy appears to be promising for the improvement of anemia and thrombocytopenia with low/intermediate myelodysplastic syndromes.


Amalia H, Sasaki R, Suzuki Y, Demizu Y, Bito T, Nishimura H, et al.  Vitamin K2-derived compounds induce growth inhibition in radioresistant cancer cells.  Kobe J Med Sci.  2010 Sep 28;56(2):E38-49.

Newly synthesized VK2 derivatives seemed to be potential anti-tumor agents in various cancers and radioresistant cancers.  The efficacy of these compounds is related to the generation of reactive oxygen species. 


Ames BN.  Prevention of mutation, cancer, and other age-associated diseases by optimizing micronutrient intake.  J Nucleic Acids.  2010;2010:725071.

Optimizing micronutrient intake will optimize metabolism, resulting in decreased DNA damage and less cancer, as well as other degenerative diseases of aging.  The Triage Theory provides a unifying rationale for a causal link between chronic, modest deficiency of a micronutrient (approximately 40 essential minerals, vitamins, amino acids, and fatty acids) and the many degenerative diseases that accompany aging such as cancer, immune dysfunction, cognitive decline, cardiovascular disease and stroke.  If the theory is correct, the incidence of these diseases might be reduced by an inexpensive micronutrient intervention, such as a vitamin supplement.


Bar-Sela G, Epelbaum R, Schaffer M.  Curcumin as an anti-cancer agent:  review of the gap between basic and clinical applications.  Curr Med Chem.  2010;17(3):190-7. 

Curcumin is an herbal remedy.  Extensive research has revealed important functions of curcumin, such as being anti-inflammatory, cytokines release, antioxidant, immunomodulatory, enhancing apoptotic process and anti-angiogenic properties.  Curcumin also mediates chemo and radiation resistance in colon and pancreatic, and cervical cancer.  This study found that it produced a response in less than 10% of patients with advanced pancreatic cancer, and had a minor effect on survival. 


Cazzola M, Malcovati L.  Prognostic classification and risk assessment in myelodysplastic syndromes.  Hematol Oncol Clin North Am.  2010 Apr;24(2):459-68.


Cerhan JR, O’Connor HM, Fredericksen ZS, Liebow M, Macon WR, Wang AH.  Vitamin K intake and risk of non-Hodgkin lymphoma (NHL).  Cancer Res.  2010 Apr;70(8):Supp 1. 

Vitamin K is critical to the functioning of several key proteins in the coagulation cascade.  Vitamin K also inhibits inflammatory cytokines and affects factors that foster cell cycle arrest and apoptosis, which are pathways to the development of lymphomas.  They tested the hypothesis that dietary and supplemental intake of vitamin K was inversely associated with risk of NHL and common subtypes.  They evaluated the dietary and supplemental intake of vitamin K and NHL risk in a clinic based study of 603 newly diagnosed NHL cases and 1007 controls at the Mayo Clinic.   The results showed that higher intake of vitamin K from the diet was inversely associated with risk of NHL and for the major subtypes.  The risk of developing NHL was approximately 45% lower for participants who had vitamin K intakes greater than 108 ug/day, compared to those who had intakes below 39 ug/day.  This association remained after accounting for other factors such as age, sex, education, obesity, smoking, alcohol use and food intake.


Chu KJ, Lai EC, Yao XP, Zhang HW, Lau WY, Fu XH, et al.  Vitamin analogues in chemoprevention of hepatocellular carcinoma after resection or ablation – a systematic review and meta-analysis.  Asian J Surg.  2010 Jul;33(3):120-6.

Oral administration of vitamin A analogues and MK4 have been tested as chemopreventive agents after the hepatic resection for HCC.  There were 4 randomized, controlled trials, conducted in Japan.  Four trails evaluated the preventive efficacy of MK4 on HCC recurrence.  The results showed significantly better tumor recurrence-free survival from vitamin A or MK4.


Grivennikov SI, Karin M.  Inflammation and oncogenesis:  a vicious connection.  Curr Opin Genet Dev.  2010 Feb;20(1):65-71. 

Epidemiological and experimental data suggest a close connection between inflammation and the development of tumors.  Solid tumors are typically infiltrated with immune cells and inflammation impacts most, if not all, stages of tumorigenesis.  In this review they discuss the mechanisms of cancer promoting inflammation.


Hoyt MT, Palchaudhuri R, Herenrother PJ.  Cribrostatin 6 induces death in cancer cells through a reactive oxygen species (ROS)-mediated mechanism.  Invest New Drugs.  2011 Aug;29(4):562-73.   

 

Hung Y-J, Lee C-H, Chu N-F, Shieh Y-S.  Plasma protein Growth Arrest-Specific 6 levels are associated with altered glucose tolerance, inflammation, and endothelial dysfunction.  Diabetes Care.  Aug 2010;33(8):1840-1844.

Protein growth arrest-specific 6 (Gas6) was the latest addition to the list of known vitamin K dependent proteins.  Reports suggest that Gas6 is involved in the pathogenesis of diabetic renal and vascular disease. This study found that plasma Gas6 (in the blood) was associated with altered glucose tolerance, inflammation and endothelial dysfunction.  The results suggest that Gas6 may be an important point for intervention in patients with diabetes. 


Nimptsch K, Rohrmann S, Kaaks R, Linseisen J.  Dietary vitamin K intake in relation to cancer incidence and mortality:  results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg).  Am J Clin Nutr.  2010 May;91(5):1348-58.

24,340 participants in the EPIC-Heidelberg cohort study, free of cancer at enrollment, were actively followed up for cancer incidence and mortality through 2008.  Dietary vitamin K intake was followed.  Dietary intake of menaquinones, highly determined by the consumption of cheese, was nonsignificantly inversely associated with overall cancer incidence.  Cancer risk reduction occurred with increasing intake of menaquinones, and was more pronounced in men than in women, mainly due to significant inverse associations with prostate and lung cancer.  There was no association with phylloquinone intake.  The dietary intake of menaquinones was associated with a reduced risk of cancer and a reduced risk of dying from cancer.

 

Novotny JA, Kurilich AC, Britz SJ, Baer DJ, Clevidence BA.  Vitamin K absorption and kinetics in human subjects after consumption of 13C-labelled phylloquinone from kale.  Br. J Nutr.  2010 Sep;104(6):858-62.

The absorption and plasma disappearance of vitamin K was investigated.  Average peak plasma concentration of the six subjects was 2.1 nmol/l.  Modeling results demonstrated a mean bioavailability of phylloquinone from kale to be 4.7%.  Plasma and tissue half-times for phylloquinone were found to be 8.8 and 215 h, respectively.


Kitigawa J, Hara T, Tsurumi H, Ninomiya S, Ogawa K, Adachi S, et al.  Synergistic growth inhibition in HL-60 cells by the combination of acyclic retinoid and vitamin K2.  J Cancer Res Clin Oncol.  2011 May;137(5):779-87.


Langley RR, & Fidler IJ.  The seed and soil hypothesis revisited – the role of tumor-stroma interactions in metastasis to different organs.  Int J Cancer.  2011 June 1;128(11):2527-35. 

Patterns of metastasis are thought to be the product of favorable interactions between metastatic tumor cells (the ‘seed’) and their organ microenvironment (the ‘soil).  Many first-line therapeutic regimens currently in use for the treatment of human cancer are designed to target cancer cells or the ‘seed’ (such as chemotherapy) and also to modulate the tumor microenvironment or the ‘soil’ (such as anti-angiogenic therapy).    The most frequent target organs of metastasis are bone brain, liver, and the lung. 


Matsuda T, Konda A, Tsunashima Y, Togari A.  Inhibitory effect of vitamin K2 on interleukin-1beta-stimulated proliferation of human osteoblasts.  Biol Pharm Bull. 2010;33(5):804-8.


Health, United States, 2013.  [Internet].  United States Department of Health and Human Services.  Centers for Disease Control and Prevention (CDC).  National Center for Health Statistics. [Cited 2014 Jun 8].  Available from:  http://www.cdc.gov/nchs/

 

Rennenberg RJ, Schurgers LJ, Kroon AA, Stehouwer CD.  Arterial calcifications.  J Cell Mol Med.  2010a Sep;14(9):2203-10.

Rennenberg RJ, van Varik BJ, Schurgers LJ, Hamulyak K, Ten Cate H, Leiner T, et al.  Chronic coumarin treatment is associated with increased extracoronary arterial calcification in humans.  Blood.  2010b Jun 17;115(24):5121-3.


Schetter AJ, Heegaard NH, Harris CC.  Inflammation and cancer:  interweaving micro RNA, free radical, cytokine and p53 pathways.  Carcinogenesis.  2010 Jan;31(1):37-49.

Chronic inflammation and infection are major causes of cancer. 


Showalter SL, Wang Z, Costantino CL, Witkiewcz AK, Yeo CJ, Brody JR, et al.  Naturally occurring K vitamins inhibit pancreatic cancer cell survival through a caspase-dependent pathway.  J Gastro and Hep.  2010 Apr;25(4):738-44.

Available medical therapies against pancreatic cancer are largely ineffective and have many side effects. They explored whether the well tolerated and naturally occurring VK1 and VK2 inhibits pancreatic cancer survival.  Tested four pancreas cancer cell lines.  Two were sensitive to K1 and K2, although VK2 was the more potent compound.  They found that non-toxic vitamin K induced apoptosis in over 60% of cells in the sensitive lines.  Concluded that naturally-occurring, non-toxic, safe K vitamins can lead to cancer cell death, and could benefit patients with pancreatic cancer, either as a single agent or in combination with chemotherapy.  This combination could be effective, for both treatment, or to prevent the recurrence of cancer, after surgery.


Tabasum A, Qadir MI.  Deficiency of vitamin K linked to cancer, osteoporosis and heart diseases.  Int J Curren Pharma Rev and Res.  2010;1(1):24-32.

Studies demonstrate that vitamin K has been established to include an anti-cancer effect in the lab and in animals.  Studies have concluded that the intake of vitamin K in food is coupled with a lesser risk of occasional and critical cancer. 


Tulchinsky, TH.  Micronutrient deficiency conditions:  Global health issues.  Public Health Reviews.  2010;32:243-55

Micronutrient deficiency conditions are widespread among 2 billion people in developing and in developed countries.  There are silent epidemics of vitamin and mineral deficiencies affecting people of all genders and ages, as well as certain risk groups.  They not only cause specific diseases, but they act as exacerbating factors in infectious and chronic diseases, greatly impacting morbidity, mortality, and quality of life.  Micronutrient deficiency conditions are related to many chronic diseases such as osteoporosis, thyroid deficiency, cancer and cardiovascular diseases.  Deficiencies in some groups of people at special risk require supplementation.  Fortification with vitamins has a long record of success and safety, and has been proven effective for the prevention of specific diseases. 


Wei G, Wang M, Hyslop T, Wang Z, Carr BI.  Vitamin K enhancement of sorafenib-mediated HCC cell growth inhibition in vitro and in vivo.  Int J Cancer.  2010 Dec 15;127(12):2949-58.

Sorafenib is the first oral agent to show activity against human hepatocellular carcinoma (HCC).  Apoptosis has been induced in HCC by both Sorafenib, as well as by naturally occurring K vitamins.  There are few nontoxic agents with activity against HCC growth, so they evaluated these agents combined and independently.  They found that vitamin K enhanced Sorafenib effects on growth inhibition  in several HCC cell lines.  While Sorafenib alone was ineffective, adding vitamin K1 caused major tumor regression.


Wei G, Wang M, Carr BI.  Sorafenib combined vitamin K induces apoptosis in human pancreatic cancer cell lines through RAF/MEK/ERK and c-Jun NH2-terminal kinase pathways.  Journal of Cell Physiology.  2010 July;224(1):112-9.

Few agents have activity against pancreas cancer cell growth, so they evaluated naturally occurring K vitamins (K1, K2, and K5) and Sorafenib, both independently and together on the cancer cell growth.  They found that when a K vitamin was combined with Sorafenib, the dose required for Sorafenib for growth inhibition was substantially reduced.  The combination is attractive for evaluating against pancreas cancer growth clinically, with patients.


Carr BI, Wang Z, Wang M, Cavallini A, D’Alexxandro R, Refolo MG.  c-Met-Akt pathway-mediated enhancement of inhibitory c-Raf phosphorylation is involved in vitamin K1 and sorafenib synergy on HCC growth inhibition.  Cancer Biol Ther.  2011 Sep 15;12(6):531-8.

Sorafenib is an approved agent for treatment of HCC, but tumor shrinkage is minor.  So they developed a strategy to combine K vitamins with Sorafenib to treat HCC and found that this combination enhanced HCC cell growth inhibition. 


Hanahan D, Weinberg RA.  Hallmarks of cancer:  the next generation.  Cell.  2011 Mar 4;144(5):646-74.


Kitigawa J, Hara T, Tsurumi H, Ninomiya S, Ogawa K, Adachi S, et al.  Synergistic growth inhibition in HL-60 cells by the combination of acyclic retinoid and vitamin K2.  J Canc Res and Clin Onc.  2011 May;137(5):779-87.


Langley RR, Fidler IJ.  The seed and soil hypothesis revisited – the role of tumor-stroma interactions in metastasis to different organs.  Int J Cancer.  2011 Jun 1;128(11):2527-35.

While some types of tumors are capable of forming metastases in virtually every organ in the body, the most frequent target organs of metastasis are bone, brain, liver, and the lung. 

 

Yoshida H, Shiratori Y, Kudo M, Shiina S, Mizuta T, Kojiro M, et al.  Effect of vitamin K2 on the recurrence of hepatocellular carcinoma.  Hepatology.  2011 Aug;54(2):532-40. 

Hepatocellular carcinoma is characterized by frequent recurrence, even after curative treatment.  Vitamin K2 may be effective in preventing HCC recurrence.  Patients  were given 45 mg per day or 90 mg day vitamin K2, or a placebo, in a double blind fashion.  There were 181, 185 and 181 patients in each group, respectively.  Interim analysis indicated that vitamin K2 did not prevent disease occurrence or death.  They could not confirm the efficacy of vitamin K2 in suppressing HCC recurrence.

Cancela ML, Conceicao N, Laize V.  Gla-rich protein, a new player in tissue calcification.  Adv Nutr.  2012 Mar;3(2):174-81.

Gla-rich protein (GRP) was recently identified in sturgeon, mice and humans.  We know it has exceptional capacity in binding the calcium ion through a dense network of Gla residues.  The high content of Gla residues and its accumulation at sites of pathological calcification in different human pathologies affecting skin or the vascular system and in breast cancer tumors suggest that GRP may function as a modulator of calcium availability.  Although the influence of GRP on the progression of these diseases will need to be further elucidated, it raises the possibility that GRP could be used as a molecular biomarker and/or target for disease prevention and therapy.  

Du W, Zhou Jr, Wang DL, Gong K, Zhang QJ.  Vitamin K1 enhances sorafenib-induced growth inhibition and apoptosis of human malignant glioma cells by blocking the Raf/MEK/ERK pathway.  World J Surg Oncol.  2012 Apr 21;10:60.

Sorafenib as a single agent, showed antitumor activity in a dose-dependent manner in glioma cells (brain cancer), but the effects were more pronounced when used in combination with vitamin K1 treatment.  Together they produced a marked growth inhibition and cancer cell death.


Nakaya K, Masuda Y, Aiuchi T, Itabe H.  Vitamin K2 as a chemotherapeutic agent for treating ovarian cancer.  [Internet].  In:  Farghaly SA.  Ovarian cancer – clinical and therapeutic perspectives.  InTech; [cited 2014 June 4].  Available from:  http://www.intechopen.com/books/ovarian-cancer-clinical-and-therapeutic-perspectives

Several ovarian cancer cell lines are sensitive to vitamin K2, which utilizes a different mechanism from those of conventional chemotherapeutic agents for ovarian cancer, meaning that vitamin K2 in combination with standard treatments, such as cisplatin and etoposide, may be an effective treatment for ovarian cancers.  Plus, none of the clinical trials show any side effects from vitamin K.  These authors recommend using VK2 as a chemotherapeutic agent for ovarian cancer.  


Karasawa S, Azuma M, Kasama T, Sakamoto S, Kabe Y, Imai T, et al.  Vitamin K2 covalently binds to Bak and induces Bak-mediated apoptosis.  Mol Pharmacol.  2013 Mar;83(3):613-20.


Riaz IB, Riaz H, Riaz T, Rahman S, Amir M, Badshah MB, et al.  Role of vitamin K2 in preventing the recurrence of hepatocellular carcinoma after curative treatment:  a meta-analysis of randomized controlled trials.  BMC Gastroenterol.  2012 Nov 29;12:170.

This was an effort to do a systematic review which focused on Vitamin K2 as a chemopreventive agent for HCC.  Five randomly controlled trials evaluated the preventive efficacy of MK4 on HCC recurrence after hepatic resection or local ablative therapy.  The meta-analysis of all five studies, failed to confirm significantly better tumor recurrence-free survival at one year.  There was insufficient data to determine tumor recurrence at the 2nd and 3rd year.  The authors encouraged higher quality randomized controlled trials.


Siegel, R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al.  Cancer treatment and survivorship statistics, 2012.  CA Cancer J Clin.  2012 Jul-Aug;62(4):220-41.

The number of cancer survivors continues to increase due to the aging and growth of the population and improvements in survival rates.  The three most prevalent cancers among males are prostate (43%), colorectal (9%), and melanoma of the skin (7%) and those among females are breast (41%), uterine corpus (8%), and colorectal (8%).  This article summarizes common cancer treatments, survival rates and post treatment concerns and introduces the National Cancer Survivorship Resource Center.


Xia J, Matsuhashi S, Hamajima H, Iwane S, Takahashi H, Eguchi Y, et al.  The role of PKC isoforms in the inhibition of NF-kB activation by vitamin K2 in human hepatocellular carcinoma cells.  J Nutr Biochem.  2012 Dec;23(12):1668-75.


Yao Y, Li L, Zhang H, Jia R, Liu B, Zhao X, et al.  Enhanced therapeutic efficacy of vitamin K2 by silencing BCL-2 expression in SMMC-7721 hepatocellular carcinoma cells.  Oncol Lett.  2012 Jul;4(1):163-67.

Vitamin K2 exerts cell growth inhibitory effects in various human cancer cells.  In this study, a new strategy of gene therapy was tested by combining a protein that is frequently overexpressed in numerous tumors with VK2.  This combined treatment significantly enhanced cytotoxicity compared with either agents alone.  It appears that the combination has stronger antitumor effects, and offers a promising approach in cancer gene therapy.   


American Cancer Society.  Infectious agents and cancer:  viruses.  Revised 3/7/2013 [Internet].  [cited 2014 May 23].  Available from:  http://www.cancer.org/cancer/cancercauses/othercarcinogens/infectiousagents/infectiousagentsandcancer/infectious-agents-and-cancer-viruses


Beulens JWJ, Booth, SL, van den Heuvel EGHM, Stoecklin E, Baka A, Vermeer C.  The role of menaquinones (vitamin K2) in human health.  Br J Nutr.  2013 Oct;110(8):1357-68.

Recent reports have attributed the health benefits of vitamin K beyond its function to activate coagulation factors.  Several studies suggest that menaquinones, also known as vitamin K2, may be more effective in activating extra-hepatic vitamin K-dependent proteins than phylloquinone, (K1).  The present review describes the current knowledge on menaquinones based on dietary reference values, including optimal dietary intake, nutrient amount required to prevent deficiency, optimal body stores to prevent chronic disease, and factors influencing requirements such as absorption, metabolism, age and sex.  There are significant gaps in the current knowledge on menaquinones, leading to a call for further research, and the merit of considering the role of menaquinones when developing recommendations for vitamin K intake.


Karasawa S, Azuma M, Kasama T, Sakamoto S, Kabe Y, Imai T, et al.  Vitamin K2 covalently binds to Bak and induces Bak-mediated apoptosis.  Mol Pharma.  2013 Mar;83(3):613-620.

Vitamin K2 is known to have anticancer activity in vitro and in vivo.  This study looks at the underlying molecular mechanism, which seems to include Bak as a molecular target of VK2- induced apoptosis.  Bak is part of the gene family involved with cell death.  VK2 directly interacts with Bak and induces mitochondrial-mediated apoptosis.  The evidence suggests that the attachment of VK2 is critical for apoptosis induction and this study provides insight into the anticancer effects of VK2.


Wang X, Liu J WAng Z, Huang Y, Liu W, Zhu X, et al.  Periostin contributes to the acquisition of multipotent stem cell-like properties in human mammary epithelial cells and breast cancer cells.  PLoS One.  2013 Aug;8(8):e72962.

Periostin (POSTN) is a recently identified vitamin K dependent protein, originally isolated from osteoblast cells as an important regulator of bone and tooth formation and maintenance.  Research shows that it is also involved with cardiac healing, embryonic development, inflammation and tissue injury, and cancer.  Periostin is frequently dysregulated in various malignant cancers and promotes tumor metastatic growth, and is an active agent in breast cancer.  This study provides a new view for understanding the multifaceted roles of Perostin in breast cancer progression, as it seems to modulate the mesenchymal state and the differentiation potentials of mesenchymal stem cells, which are loosely packed, unspecialized cells found in embryonic connective tissue.


Zhong JH, Mo XS, Xiang BD, Yuan WP, Jiang JF, Xie GS, et al.  Postoperative use of the chemopreventive vitamin K2 analog in patients with hepatocellular carcinoma.  Plos One.  2013;8(3):e58082.

This study evaluated the efficacy of vitamin K2 in patients with liver cancer after curative resection or ablation.  They reviewed six randomly controlled trials and one cohort study and the data showed that VK2 therapy was associated with a significant reduction in the 2 and 3 year tumor recurrence rates and with a significant improvement in the 1, 2, and 3 year overall survival rate. 

 

Samykutty A, Shetty AV, Dakshinamoorthy G, Kalyanasunddaram R, Zheng G, Chen A, et al.  Vitamin K2, a naturally occurring menaquinone, exerts therapeutic effects on both hormone-dependent and hormone-independent prostate cancer cells.  Evid Based Complement Alternat Med.  2013;2013:287358.

In recent years, several studies have shown that vitamin K2 has anticancer activity in a variety of cancer cells.  In this study they sought to characterize the anticancer potential of K2 in both androgen-dependent and –independent prostate cancer cells.  The results suggest that K2 is an anti-inflammatory agent, as several inflammatory genes are downregulated in prostate cancer cells following treatment with K2.  Vitamin K2 administration resulted in significant inhibition of both androgen-dependent and androgen-independent tumor growth, meaning that  K2 may be a therapeutic agent in the treatment of prostate cancer.


Wikipedia.  Menadione. 2014 Apr 23 [cited 2014 May 13].  Available from
http://en.wikipedia.org/wiki/Menadione


Cancer facts and figures 2014.  American Cancer Society. 2014. [cited 2014 May 15];
Available from www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf


Infectious agents and cancer.   American Cancer Society.  [cited 2014 May 15] Available from
http://www.cancer.org/acs/groups/cid/documents/webcontent/002782-pdf.pdf


Higdon J.  Vitamin K.  Linus Pauling Institute [Internet[.  May 2004.  [updated 2011 Dec 19; cited 2014 May 29].  Available from  (
http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK  


Juanola-Falgarona M, Salas-Salvado J, Martinez-Gonzalez MA, Corella D Estruch R, Ros E, et al.  Dietary intake of vitamin K is inversely associated with mortality risk.  J. Nutri.  2014 Mar 19.  Epub.

Vitamin K has been related to cardiovascular disease and cancer risk.  The present study assessed the association between the dietary intake of different types of vitamin K and mortality in a Mediterranean population at high risk for cardiovascular disease.  A cohort analysis was conducted in 7216 participants from the PREDIMED study, with a follow-up of 4.8 years.  Their ages ranged from 55-80.  Dietary phylloquinone intake was inversely associated with a significantly reduced risk of cancer and all cause mortality.  In longitudinal assessments, individuals who increased their intake of phlloquinone or menaquinone during follow up had a significantly lower risk of cancer than individuals who decreased or did not change their intake, for both men and women. 


Cancer:  fact sheet.  World Health Organization: updated Feb 2014.  [cited 2014 May 30].  Available from:  www.Who.int/mediacentre/factsheets/fs297/en


Ames BN.  Vitamin and mineral inadequacy accelerates aging-associated disease.  In:  The World Book on Health Aging, in press.  2014.

 
Frei B, Ames BN, Blumberg JB, Willett, WC.   Ideas and Opinions:  Enough is enough: Time to consider all the data and avoid sweeping conclusions about vitamin and mineral supplements. Ann Intern Med.  Posted 2014 Feb 6.  [cited 2014 June 1].  Available from:  http://annals.org/article.aspx?articleid=1789253&resultClick=3

In their editorial, Guallar et al. concluded “the case is closed––supplementing the diet of well-nourished adults with (most) mineral or vitamin supplements has no clear benefit and might even be harmful” (1).  However, the authors erroneously ignored decades of nutrition research and diet monitoring of the U.S. population to reach this misleading conclusion.  Taking a daily Multi-vitamin not only helps fill known nutritional gaps in the diet of most Americans, thereby assuring normal body function and supporting good health, but vitamins may also have the added benefit of helping to reduce the risk of some chronic diseases.  To call “the case…closed,” is not based on the established science and misinforms both the public and the medical community.


Liu Y, Coldita GA, Cotterchio M, Boucher BA, Kreiger N.  Adolescent dietary fiber, vegetable fat, vegetable protein, and nut intakes and breast cancer risk.  Breast Cancer Res Treat.  2014 Jun;145(2):461-70.

The importance of early-life exposures in breast cancer development is increasingly recognized.  This population-based case-control study investigated the associations of dietary fiber, vegetable protein, vegetable fat, and nuts consumed during adolescence with breast cancer risk.  Diet at ages 10-15 were assessed.  The results showed that dietary fiber, vegetable protein, vegetable fat, and nuts consumed during adolescence were associated with reduced breast cancer risk.

Viegas CS, Herfs M, Rafael MS, Enriquez JL, Teixeira A, Luis IM, et al.  Gla-rich protein is a potential new vitamin K target in cancer:  evidences for a direct GRP-mineral interaction.  Biomed Res Int.  2014;2014:340216. 

Gla-rich protein (GRP) was identified in sturgeon as a new vitamin K dependent protein (VKDP) with a high density of Gla residues and is associated with ectopic or abnormal calcifications in humans.  Vitamin K dependent proteins require sufficient intake of vitamin K to be carboxylated and activated.  Uncarboxylated GRP was the predominant form associated with cancerous tumor cells, suggesting a pivotal role for GRP in the regulation of mineralization that may be compromised when intake of VItamin K is low.  The data indicates that GRP may represent a new target for the anticancer potential of vitamin K.


Donald MS.  Vitamin K:  the missing link to prostate health.  Med Hypotheses.  2015 Mar;84(3):219-22.

Age related prostate enlargement is very common in Western societies.  There is no biological, mechanistic explanation that deals with the root causes and progression of this very common disorder among men.  All treatments are based on symptomatic relief, not a fundamental understanding of the cause of the disease.  Recent advances have shown that varicose veins in the sperm cord, or varicoceles, are more common than realized.  But what causes them?  Recent research has uncovered the role of vitamin K in the calcification of varicose veins as well as in the proliferation of smooth muscle cells in the vein wall.  Vitamin K is intimately involved int he formation of varicose veins.  The hypothesis is that poor prostate health is essentially a vitamin K insufficiency disorder.  By providing vitamin K, along with other supporting nutrients, it is likely that excellent prostate health can be extended and perhaps poor prostate health can be reversed.  It is recommended that studies examine the connection between vitamin K and veins in the prostate.