摘要
白血病干细胞(LSC)是急性骨髓性白血病(AML)治疗失败和复发的原因。因此,新LSC靶向治疗策略的开发具有提高AML治疗效果的重大临床重要性。在临床前研究中,组蛋白脱乙酰酶(HDAC)抑制剂表现出了强力且特异的抗癌干细胞活性。西达本胺,一种新苯甲酰胺型选择性HDAC抑制剂,已被报道在相对成熟的起源群体中能诱导G1期阻滞和细胞凋亡,然而它对原始LSC的作用未被阐明。在该研究中,我们证明西达本胺以具有浓度和时间依赖性的方式特异地诱导LSC样细胞和主要AML CD34+细胞的凋亡。我们进一步的分子机制研究揭示了西达本胺通过活化活性氧(ROS)诱导LSC死亡。它通过调节线粒体膜电位,调节B淋巴细胞瘤-2基因(BLC2)家族中的抗凋亡及促凋亡蛋白,激活胱天蛋白酶3(caspase-3)等方式导致DNA聚合酶(PARP)降解。同时,西达本胺活化CD40并调节它的下游信号通路JNK和NFκB。该研究的结果表明西达本胺可能是治疗AML的新LSC靶向剂。
关键词: 急性骨髓性白血病,CD40,组蛋白脱乙酰酶抑制剂,白血病干细胞,线粒体,活性氧
Current Cancer Drug Targets
Title:A New Strategy to Target Acute Myeloid Leukemia Stem and Progenitor Cells Using Chidamide, a Histone Deacetylase Inhibitor
Volume: 15 Issue: 6
Author(s): Yin Li, Kai Chen, Yong Zhou, Yiren Xiao, Manman Deng, Zhiwu Jiang, Wei Ye, Xiangmeng Wang and Xinru Wei, Jie Li, Jiabao Liang, Zhongxin Zheng, Yao Yao, Weiguang Wang, Peng Li and Bing Xu
Affiliation:
关键词: 急性骨髓性白血病,CD40,组蛋白脱乙酰酶抑制剂,白血病干细胞,线粒体,活性氧
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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Yin Li, Kai Chen, Yong Zhou, Yiren Xiao, Manman Deng, Zhiwu Jiang, Wei Ye, Xiangmeng Wang and Xinru Wei, Jie Li, Jiabao Liang, Zhongxin Zheng, Yao Yao, Weiguang Wang, Peng Li and Bing Xu , A New Strategy to Target Acute Myeloid Leukemia Stem and Progenitor Cells Using Chidamide, a Histone Deacetylase Inhibitor, Current Cancer Drug Targets 2015; 15 (6) . https://dx.doi.org/10.2174/156800961506150805153230
DOI https://dx.doi.org/10.2174/156800961506150805153230 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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