Establishment of Vitamin K2 Therapy in Myelodysplastic Syndromes

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We originally reported that vitamin K2 (VK2) analogs, including menaquinone 4 (MK4) but not vitamin K1, effectively induce apoptosis in various types of primary cultured leukemia cells and leukemia cell lines in vitro. Several case reports also demonstrated the clinical benefits of using VK2 for the treatment of patients with leukemia and myelodysplastic syndrome (MDS). It is of interest that VK2 treatment with/ without vitamin D3 (D3) has been reported to be effective for improvement of cytopenia in patients with refractory anemia (RA) in MDS, although the underlying mechanism is still unclear. We here focus on the combined effects of VK2 and D3 on leukemia cells. Treatment of HL-60 and U937 cells with VK2 plus 1α, 25-dihydroxy-vitamin D3 (D3) plus VK2 dramatically enhanced monocytic differentiation -a more than 20-fold increase of the mean intensities of CD14 as compared to the cells treated with either VK2 or D3 alone by flow cytometry -and also achieved complete monocytic maturatio … More n as assessed by morphology. In addition, enhanced accumulation of G1 arrest was detected after 48 to 72 hr-exposure to VK2 plus D3. These combined effects far exceed the maximum differentiation-inducing ability at the optimal concentrations of each vitamin alone. It was of interest that, along with cell differentiation, the cells became resistant against various apoptosis stimuli including VK2-and H2O2-treatment and serum deprivation. Furthermore, dramatic accumulation of cytoplasm p21^<CIP1> along with disappearance of nuclear p21^<CIP1> was detected in response to 96-hr treatment with VK2 plus D3. This anti-apoptotic effect was mediated in part by blocking JNK activity, which is regulated by interaction of p21^<CIP1> and ASK-1, an upstream serine/threonine kinese in the JNK pathway. A stable transfectant of U937-ΔNLS-p21^<CIP1>, which lacks a nuclear localizing signal of p21^<CIP1> and results in over-expression of cytoplasm p21^<CIP1> without monocytic differentiation, showed resistance against apoptosis inductions. These data suggest that a change of intracellular distribution of p21CIP from nucleus to cytoplasm along with differentiation appears to be functioning as anti-apoptotic behavior. Our data suggest that VK2 plus D3 might be a potent combination for the differentiation-based therapy for AML and MDS. Furthermore, an anti-apoptotic effect during enforced differentiation/maturation induction might explain the improvement of cytopenia in RA patients, whose cytopenias are mediated through apoptosis. Less