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

维生素K2对骨髓增生异常综合征患者的作用-从维生素K2对白血病细胞的凋亡诱导作用的角度-

• 批准号: 11671017
• 负责人: MIYAZAWA Keisuke
• 金额: $ 2.24万
• 依托单位: Tokyo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671017/
• 关键词: vitamin K2; myelodysplastic syndromes; leukemia; apoptosis; differentiation; vitamin D3

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.

我们最初报道了维生素K2 （VK2）诱导原代培养的白血病细胞和白血病细胞系凋亡。这种凋亡过程是通过下调BCL-2抑制、上调BAX、线粒体膜电位去极化和激活caspase-3介导的。H-60细胞中BCL-2的过度表达（HL-60bcl-2）几乎完全抑制了VK2对细胞凋亡的诱导作用。然而，HL-60bcl-2细胞仍通过G0/G1阻滞向单核细胞分化。这强烈表明VK2。此外，我们已经报道，通过VK2和维生素D3类似物联合治疗，这种单核细胞分化诱导可以协同增强。有趣的是，VK2诱导的细胞凋亡被显著抑制，同时单核细胞分化增强。根据我们的体外观察，VK2治疗骨髓增生异常综合征（MDS）和MDS后AML的初步研究在日本的许多机构进行。这些临床试验证明了VK2对MDS患者的治疗效果。进一步的基于分子的研究仍在继续解释VK2在MDS中的治疗作用机制。

项目成果

Otawa M, Kawanishi Y, Iwase O, Shoji N, Miyazawa K, Ohyashiki K.: "Comparative multi-color flow cytometric analysis of cell sruface antigens in bone marrow hematopoietic progenitors between refractory anemia and aplastic anemia."Leuk Res.. 24. 359-356 (20

Otawa M、Kawanishi Y、Iwase O、Shoji N、Miyazawa K、Ohyashiki K.：“难治性贫血和再生障碍性贫血之间骨髓造血祖细胞表面抗原的比较多色流式细胞术分析。”Leuk Res.. 24。

Nishimaki J, Miyazawa K, Yaguchi M, Katagiri T, Kawanishi Y, Toyama K, Ohyashiki K, Hashimoto S, Nakaya K, Takiguchi T.: "Vitamin K2 induces apoptosis of a novel cell line established from a patient with myelodysplastic syndrome in blastic transformation.

Nishimaki J、Miyazawa K、Yaguchi M、Katagiri T、Kawanishi Y、Toyama K、Ohyashiki K、Hashimoto S、Nakaya K、Takiguchi T.：“维生素 K2 诱导从骨髓增生异常综合征患者建立的新型细胞系凋亡

Otawa K,Kawanishi Y,Shoji N,Miyazawa K,Ohyashiki K :: "Comparative multi-color analysis of cell surface antigens in bone marrow hematopoietic progenitors between refractory anemia and aplastic anemia."Leukemia Res.. 24. 359-366 (2000)

Otawa K、Kawanishi Y、Shoji N、Miyazawa K、Ohyashiki K ::“难治性贫血和再生障碍性贫血之间骨髓造血祖细胞中细胞表面抗原的比较多色分析。”白血病研究.. 24. 359-366 (2000

Katagiri T, Miyazawa K, Nishimaki J, Yaguchi M et al.: "Cambination of granulocyte colong-stimulating factor and low-dose cytosine arabinosida further enhance myeloid differentiation in leeckenia cells in vitro"Leukemia Lymphoma. (in press). (2000)

Katagiri T、Miyazawa K、Nishimaki J、Yaguchi M 等人：“粒细胞结肠刺激因子和低剂量阿拉伯糖胞嘧啶的组合可进一步增强体外 leeckenia 细胞的骨髓分化”白血病淋巴瘤。

Otawa K, Kawanishi Y, Shojin N, Miyazawa K, et al.: "Comparatine multi-color analysis of cell surface antigens in bone marrow hematopoietic progenitors between refractoryanemia and aplastic anemia"Leukemia Res.. (in press). (2000)

Otawa K、Kawanishi Y、Shojin N、Miyazawa K 等人：“难治性贫血和再生障碍性贫血之间骨髓造血祖细胞表面抗原的比较多色分析”白血病研究（正在出版）。