A New Strategy to Target Acute Myeloid Leukemia Stem and Progenitor Cells Using Chidamide, a Histone Deacetylase Inhibitor
A New Strategy to Target Acute Myeloid Leukemia Stem and Progenitor Cells Using Chidamide, a Histone Deacetylase Inhibitor
复制标题
使用组蛋白脱乙酰酶抑制剂西达本胺靶向急性髓系白血病干细胞和祖细胞的新策略
DOI：
10.2174/156800961506150805153230
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发表时间：
2015-01-01
影响因子：
3
通讯作者：
Xu, Bing
中科院分区：
文献类型：
--
作者：
Li, Yin;Chen, Kai;Xu, Bing
白血病干细胞（LSC）是导致急性髓细胞白血病（AML）治疗失败和复发的原因。因此，开发新的LSC靶向治疗策略对于改善AML的治疗结果具有至关重要的临床意义。组蛋白去乙酰化酶（HDAC）抑制剂在临床前研究中显示出有效和特异性的抗癌干细胞活性。Chidamide是一种新型的苯甲酰胺型选择性HDAC抑制剂，已报道其在相对成熟的祖细胞群体中诱导G1期阻滞和凋亡，而其对原始LSC的影响尚未阐明。在这项研究中，我们证明西达米特特异性诱导LSC样细胞和原代AML CD 34（+）细胞凋亡，并呈浓度和时间依赖性。我们进一步的分子机制研究发现，西达米特通过激活活性氧（ROS）诱导LSC死亡。它损害线粒体膜电位，调节BCL 2家族中的抗凋亡和促凋亡蛋白，并激活caspase-3，导致PARP降解。同时，西达米特激活CD 40并调节其下游信号通路JNK和NF κ B B。本研究的结果表明，西达米特可能是一种新的LSC靶向药物的AML治疗。
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 NF kappa B. The results of this study suggest that chidamide may be a novel LSC-targeting agent for AML therapeutics.