The anticancer effects of vitamin K

Alternative Medicine Review,  August, 2003  by Davis W. Lamson,  Steven M. Plaza

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The addition of vitamin K3 to HepG2 cells hyperphosphorylated the CDC2 kinase, inactivating the enzyme and inhibiting the cell cycle. (98) It has been proposed that menadione modifies the active sites of the CDC25 dual specificity protein phosphatases and reduces or even abolishes the dephosphorylating activity of the enzyme. Vitamin K3 binds to active sulfhydryl groups of cysteine residues at active p34CDC2 sites. (45) This action stems from binding to the catalytic domain of CDC25 phosphatase. K3 also decreased protein-tyrosine phosphatase by 2- to 3-fold (45) and suppressed the expression of proliferating cell antigen as well as cyclin B in S phase. (99)

Vitamin K2 has also been shown to work at the level of the cell cycle, acting on cyclins to inhibit the cell cycle and initiate differentiation. It is a powerful inducer of differentiation in a number of myeloid leukemia cell lines in various stages of maturation. The mechanism of differentiation by K2 differs from retinoic acid. Vitamin K2 has not been found to bind retinoic acid receptors (RAR) alpha, beta, or gamma, or retinoid X receptor (RXR) alpha receptors. (68) This work with vitamin K2 implies there is an undiscovered nuclear receptor or mechanism for differentiation.

Researchers have proposed that the p21 gene may act with vitamin K2 as an additional factor in cellular differentiation. Previously it was thought that tumor suppressor genes such as p53 and BRCA1 induce the expression of the p21 gene. It was demonstrated that vitamin K2 can also stimulate p21 in a p53-independent manner. (100) (K2 was also shown to be unable to induce p53 in MG-63 human osteosarcoma cells, while inducing p21 gene.) MG-63 cells, shown to lack the p53 gene, were inhibited by vitamin K2 at high concentrations between [10.sup.-7] and [10.sup.-5] M/L. The elevated levels of p21 resulted in the differentiation of osteosarcoma cells.

The action of vitamin K2 in cell cycle arrest acts at the G1/S transition. When K2 transcriptionally activates the p21 protein, it complexes and inhibits the phosphorylation of G1 cyclin-dependent kinases in the cell cycle. This results in the arrest of cells in the G0/G1 phase of the cell cycle.

Conclusion

Vitamin K, in all its various forms, has been shown to have anticancer effects. Vitamin K cancer research has focused on two basic mechanisms to explain these effects. The older mechanism relies on an oxidative effect produced by the one-electron cycling of vitamin K3 that surpasses the oxidative capacity of the cancer cell, leading to death. Other mechanisms have been proposed due to the anticancer effect of vitamin K forms that either do not readily cycle (K1 and K2) or that are at levels that do not initiate cycling. These clues to another mechanism have led researchers to discover an alternative mechanism of action that acts at the level of protein kinases and phosphatases. Vitamin K has been found to act on proteins such as myc and fos, which in turn leads to growth arrest and death. Cell cycle arrest has also been found to be initiated by phosphatases at the level of cyclins, which are critical in the cell cycle.