髓系白血病
组蛋白脱乙酰基酶
癌症研究
祖细胞
组蛋白脱乙酰酶抑制剂
干细胞
生物
细胞生物学
细胞凋亡
化学
组蛋白
生物化学
基因
作者
Yin Li,Kai Chen,Yong Zhou,Yiren Xiao,Manman Deng,Zhiwu Jiang,Wei Ye,Xiangmeng Wang,Xinru Wei,Jie Li,Jian Liang,Zhongxin Zheng,Yao Yao,Weiguang Wang,Peng Li,Bing Xu
出处
期刊:Current Cancer Drug Targets
[Bentham Science]
日期:2015-08-05
卷期号:15 (6): 493-503
被引量:53
标识
DOI:10.2174/156800961506150805153230
摘要
Leukemia stem cells (LSCs) are responsible for treatment failure and relapse in acute myeloid leukemia (AML). Therefore, development of novel LSCs-targeting therapeutic strategies is of crucial clinical importance to improve the treatment outcomes of AML. Histone deacetylase (HDAC) inhibitors have shown potent and specific anticancer stem cell activities in preclinical studies. Chidamide, a novel benzamide-type selectively HDAC inhibitor, has been reported to induce G1 arrest and apoptosis in the relatively mature progenitor population, whereas its effect on primitive LSCs has not been clarified. In this study, we demonstrated that chidamide specifically induces apoptosis in LSC-like cells and primary AML CD34(+) cells in a concentration- and time-dependent manner. Our further molecular mechanistic study uncovered that chidamide induces LSCs death by activation of reactive oxygen species (ROS). It compromises the mitochondria membrane potential, modulates antiapoptotic and pro-apoptotic proteins in BCL2 family and activates caspase-3 leading to PARP degradation. Meanwhile, chidamide activates CD40 and modulates its downstream signaling pathways, JNK and NFκB. The results of this study suggest that chidamide may be a novel LSC-targeting agent for AML therapeutics.
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