Mechanisms of apoptosis and differentiation induced by arsenic trioxide in leukemic cells and its clinical application

三氧化二砷诱导白血病细胞凋亡和分化的机制及其临床应用

• 批准号: 11671015
• 负责人: KIZAKI Masahiro
• 金额: $ 2.24万
• 依托单位: Keio 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 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671015/
• 关键词: arsenic trioxide; leukemia; apoptosis; differentiation; retinoic acid; GM-CSF; SCID mice; PML; RARα; 細胞周期; SCIDマウス; Bcl-2; Bax

Arsenic trioxide effectively induces clinical remission via apoptosis in relapsed acute promyelocytic leukemia (APL). However, its molecular mechniams od inducing apoptosis is still unclear. In addition, this new anti-leukemic drug is considered to be a poison, its possible adverse effects are a highly important issue related to its clinical use. Arsenic trioxide can induce apoptosis of both retinoic acid-sensitive NB4 and-resistant UF-1 cells with down-regulation of Bcl-2 and up-regulation of Bax proteins, respectively. Also, arsenic trioxide degrades APL-specific PML/RARα fusion protein. Interestingly, a combination of arsenic trioxide and GM-CSF induces differentiation, but not apoptosis of APL cells. GM-CSF was found to be associated with increased tyrosine phosphorylation of Jak2 kinase in both NB4 and UF-1 cells. A specific inhibitor of Jak2, AG490, completely blocked the ability of GM-CSF to prevent apoptosis and induce differentiation of arsenic trioxide-treated APL cells, suggesting that Jak/STAT pathway is dritical for the anti-apoptotic activity of GM-CSF in APL cells treated with both agents. These results are also observed in vivo by using human GM-CSF-producing transgenic SCID mice model. In conclusion, a combination of arsenic trioxide and GM-CSF appears to be a novel differentiation-inducing therapy in patients with APL.Further molecular studies to determine the target molecules of arsenic trioxide will be needed.

三氧化砷在中继急性临床白血病（APL）中有效地通过凋亡诱导临床缓解。然而，其分子机制OD诱导的凋亡仍不清楚。此外，这种新的抗白血病药被认为是毒药，其可能的不良影响是与其临床使用相关的非常重要的问题。砷三氧化物可以诱导视黄酸敏感的NB4和抗性UF-1细胞的凋亡，分别对Bcl-2的下调和BAX蛋白的上调。另外，砷三氧化物降解了APL特异性PML/RARα融合蛋白。有趣的是，砷三氧化物和GM-CSF的结合诱导了APL细胞的分化，但不能诱导APL细胞的凋亡。发现GM-CSF与NB4和UF-1细胞中JAK2激酶的酪氨酸磷酸化增加有关。 JAK2 AG490的特定抑制剂完全阻止了GM-CSF防止凋亡的能力，并诱导了经过三氧化物治疗的APL细胞的分化，这表明JAK/STAT途径是JAK/STAT途径的动态性，用于在两种药物治疗的APL细胞中GM-CSF的抗凋亡活性。通过使用人类GM-CSF产生的转基因SCID小鼠模型，在体内也可以观察到这些结果。总之，在APL的患者中，砷三氧化物和GM-CSF的结合似乎是一种新型的分化诱导疗法，以确定需要三氧化砷的靶标分子。

项目成果

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Kinjo K、Kizaki M、Takayama N、Michikawa N、Oda A、Okamoto S、Tahara H、Kato T、Miyazaki H 和 Ikeda Y：“全反式视黄酸治疗期间急性早幼粒细胞白血病患者的血清血小板生成素和红细胞生成素水平。

Kinje K, et al: "Serum thrombopoietin and erythropoietin levels in patients with acute promyelocytic leukaemia during all-trans retinoic acid treatment."Br.J.Haematol.. 105. 382-387 (1999)

Kinje K 等人：“全反式视黄酸治疗期间急性早幼粒细胞白血病患者的血清血小板生成素和红细胞生成素水平。”Br.J.Haematol.. 105. 382-387 (1999)

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Muto A. 等人：“1.25-二羟基维生素 D_3 诱导与 P21 和 P27 表达相关的抗视黄酸 APL 所有系 (UF-1) 的分化”血液。

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