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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

基本信息

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

项目摘要

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.

三氧化二砷通过凋亡有效诱导复发性急性早幼粒细胞白血病（APL）的临床缓解。但其诱导细胞凋亡的分子机制尚不清楚。此外，这种新型抗白血病药物被认为是一种毒药，其可能的不良反应是与其临床使用相关的一个非常重要的问题。三氧化二砷可诱导维甲酸敏感的NB 4细胞和耐药的UF-1细胞凋亡，并分别下调Bcl-2和上调Bax蛋白。此外，三氧化二砷降解APL特异性PML/RARα融合蛋白。有趣的是，三氧化二砷和GM-CSF的组合诱导APL细胞分化，但不诱导凋亡。发现GM-CSF与NB 4和UF-1细胞中Jak 2激酶的酪氨酸磷酸化增加相关。AG 490可完全阻断GM CSF对三氧化二砷处理的APL细胞的抗凋亡和诱导分化作用，提示Jak/STAT途径是GM CSF抗三氧化二砷处理的APL细胞凋亡的关键。这些结果也通过使用产生人GM-CSF的转基因SCID小鼠模型在体内观察到。结论：三氧化二砷联合GM-CSF治疗APL是一种新的诱导分化治疗方法，其作用靶分子有待于进一步的分子生物学研究。