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).
Also, the combination of VK2 along with vitamin E suppressed the growth of the primary tumor and obliterated the intraperitoneal dissemination in a 65-year-old man with ruptured HCC (Otsuka et al, 2007).
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; Zhang et al, 2012).
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).
