Micki Jacobs, Independent Researcher, Dayton, OH;
Q: You know a great deal about Vitamin K2 and its precursors in human health and disease. What is the best evidence of any value of Vitamin K2, Menadione, Menaquinone-4, and Menaquinone-7 in the prevention or treatment of any forms of cancer?
A: Evidence and interest for benefits of vitamin K2 (K2) in cancer etiology and treatment are increasing. Menadione, vitamin K3, has been added to traditional treatments in response to findings that K3>K2>K1 in antitumor effects on various cancer cell lines, but K2 is garnering attention because it is not toxic at any dose, unlike known K3 toxicity. K2 in conjunction with traditional chemotherapy has shown benefits in vitro such as in Hepatocellular Carcinoma (HCC), pancreatic cancer, lung cancer, leukemia, prostate cancer, breast cancer and in a variety of animal models such as the rat model of HCC. Certain human patients have shown benefits with K2 supplements in terms of prevention and treatment; data show that more K intake reduces risk of all-cause mortality.
These forms of vitamin K–menadione (K3), MK-4, and MK-7 (the two most studied forms of vitamin K2 of about 14 identified K2 forms) are part of the larger vitamin K family which also includes vitamin K1, the K form found in plants. Whereas K1 and K2 can be found in food, K3 is not, yet newer findings show that the human body makes menadione from consumed vitamin K in a complex process leading to body-wide endogenously created MK-4, with possible interesting connections to cancer suppression involving the enzyme UBIAD1, dubbed a ‘tumor suppressor,’ essential in this conversion of K3 into K2 and which also controls cellular cholesterol and calcium metabolism.
Vitamin K has been postulated as among the various micronutrients whose subclinical insufficiency may lead to “diseases of aging” which includes cancer. In the Triage Theory, short-term essential processes utilize micronutrients to ensure immediate survival while long-term subclinical insufficiency leads to insidious diseases of aging. Seventeen vitamin K-dependent proteins (VKDP) require K sufficiency to be optimally activated, with coagulation as short-term essential, while VKDPs beyond the coagulation cascade may remain inactivate over time, leading to disease. It appears that subclinical vitamin K insufficiency is common and there is currently no clinical test for this. One of the many VKDPs that require K sufficiency to be activated is TGFBI – mice with this protein knocked out spontaneously manifest cancer and its expression is disrupted in various cancers as either over- or under-expressed. The various VKDPs appear to have multiple roles in cancer etiology, where K may offer disease preventative effects or disease promoting effects, depending on whether cancer has initiated or the stage in which the cancer has advanced.
K2 has become more of a consideration in cancer treatment after the success in turning melodysplastic syndrome (MDS) cells into healthy cells and preventing cancer. MDS is dominated by elderly (who often do not tolerate chemotherapy well) so higher dose MK-4 was used in a 65-year-old Japanese patient whose peripheral blood blast cells had increased to show progression to acute leukemic phase. Treatment with MK-4 offered benefits of reduced blast cell count and increased platelet count with no side effects leading to speculation that “suggests the clinical benefit of using non-toxic VK2 for the treatment of MDS, especially in elderly patients.” K2, sometimes in conjunction with vitamin D, was explored with other types of cancer cell lines. In 2002, K2 intervention was expanded to more MDS patients with various forms of refractory anemia where some were given menetetrenone v none. The benefits of intervention v none were mixed, but the fact that there were significant benefits of K2 with no toxicity led to further consideration of many cancer lines.
In the case of HCC, MK-4 inhibits cancer cell lines growth. K2 showed preventative effects in women with cirrhosis at high risk of HCC in a small randomized controlled trial (RCT). HCC is plagued with recurrence, and in a double-blind RCT of ‘cured’ HCC patients comparing placebo/45 mg/90mg/d MK-4, treatment did not offer benefits at any dose. The mechanism of HCC growthappears to involve PIVKA II, produced by HCC cells in the absence of vitamin K, and suppression appears to inhibit HCC. Unfortunately, administration of MK-4 increases PIVKA II and because HCC tumors are low in vitamin K, a newer way to directly administer K2 to cancer cells was tested and found to overcome their low menaquinone uptake and offer a potentially long-term, safe anti-tumor agent, a prodrug of menahydroquinone-4, a ‘pre-form’ of MK-4. This prodrug showed benefits in HCC mice models with significant tumor inhibition and substantial decrease in PIVKA II.
Micki Jacobs’s contact info is included in the author affiliations at the top of this page.
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