Effects of Vitamin K2 in Patients with Myelodysplastic Syndromes-From The Standing Point of Apoptosis Inducing Effects of Vitamin K2 on Leukemia Cells-

我们最初报道了维生素K2（VK 2）诱导原代培养的白血病细胞和白血病细胞系的凋亡。该凋亡过程通过下调BCL-2抑制、上调BAX、线粒体膜电位去极化和激活caspase-3介导。在H-60细胞（HL-60 bcl-2）中，BCL-2的过度表达几乎完全抑制VK 2诱导的凋亡。但HL-60 bcl-2细胞仍能通过G 0/G1期阻滞向单核细胞分化。这表明VK 2。此外，我们已经报道了这种单核细胞分化诱导通过与VK 2和维生素D3类似物的组合治疗而协同增强。有趣的是，随着单核细胞分化的增强，响应于VK 2的凋亡诱导被显著抑制沿着。根据我们的体外观察结果，在日本的许多机构中进行了骨髓增生异常综合征（MDS）和MDS后AML患者的VK 2治疗初步研究。这些临床试验证实了VK 2对MDS患者的治疗效果。VK 2在MDS中的治疗作用机制仍有待进一步的分子生物学研究。

We have originally reported that vitamin K2 (VK2) induces apoptosis in primary cultured leukemia cells and leukemia cell lines. This apoptosis process was mediated through down-modulation of BCL-2 repression, up-modulation of BAX, depolarization of mitochondrial membrane potential, and activation of caspase-3. Enforced over expression of BCL-2 in H-60 cell (HL-60bcl-2) resulted in almost complete inhibition of apoptosis induction in response to VK2. However, monocytic differentiation via G0/G1 arrest was still observed in HL-60bcl-2 cells. This strongly suggests that VK2. Furthermore, we have reported that this monocytic differtntionan induction is synergistically enhanced by combined treatment with VK2 and vitamin D3 analog. Interestingly, apoptosis induction in response to VK2 was significantly suppressed along with enhanced moncytitc differentiation. In response to our in vitro observations, pilot studies of VK2 therapy in-patients with myelodysplastic syndromes (MDS) and post-MDS AML were performed in many institutions in Japan. These clinical trials demonstrate the therapeutic effects of VK2 for the patients with MDS. Further moleculer-based studies are still on going to explain the mechanisms of therapeutic effects of VK2 in MDS.