A novel HDAC inhibitor chidamide combined with imatinib synergistically targets tyrosine kinase inhibitor resistant chronic myeloid leukemia cells
A novel HDAC inhibitor chidamide combined with imatinib synergistically targets tyrosine kinase inhibitor resistant chronic myeloid leukemia cells
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新型 HDAC 抑制剂西达本胺联合伊马替尼协同靶向酪氨酸激酶抑制剂耐药的慢性粒细胞白血病细胞
DOI：
10.1016/j.biopha.2020.110390
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发表时间：
2020-09-01
影响因子：
7.5
通讯作者：
Zhou, Hongsheng
中科院分区：
文献类型：
--
作者：
He, Bailin;Wang, Qiang;Zhou, Hongsheng
Chidamide是一种新的选择性组蛋白脱乙酰酶抑制剂(HDACi)，在血液系统恶性肿瘤中具有良好的活性，但其在慢性粒细胞白血病(CML)中的作用尚未见报道。在这项研究中，我们首次证明了单独使用Chidamide抑制CML细胞的增殖，诱导细胞凋亡和细胞周期停滞。此外，奇达胺联合伊马替尼(IM)对CML细胞系KBM5和IM耐药细胞KBM5(T315I)具有协同杀伤作用，并显著降低BCR-Abl激酶活性和乙酰组蛋白H3的表达。联合治疗明显抑制IM耐药细胞中β-连环蛋白信号的构成活性，并取消间充质基质细胞(MSCs)对CML细胞的保护作用。此外，联合治疗显著降低了BCR-Abl和β-catenin转录水平，并诱导了原始CD34(+)干/祖细胞的凋亡，但对正常CD34(+)祖细胞的毒性最小。总而言之，我们的数据显示，chidamide和imatinib通过抑制bcr-Abl和β-catenin信号通路，协同靶向耐酪氨酸激酶抑制剂(TKI)的BC-CML细胞，表明这种组合具有治疗耐TKI的CML和改善BC-CML患者临床预后的潜力。
Chidamide is a novel selective histone deacetylase inhibitor (HDACi) with promising activity in hematological malignancies, but its role in chronic myeloid leukemia (CML) was marginally addressed. In this study, we firstly demonstrated that chidamide alone inhibited CML cells proliferation, induced apoptosis and cell cycle arrest. Further, chidamide combined with imatinib (IM) induced synergistic lethality in CML cell line KBM5, as well as IM-resistant CML cells KBM5(T315I), associated with a marked reduction of Bcr-Abl kinase activity and acetylhistone H3 expression. The combination treatment markedly inhibited constitutive activity of beta-catenin signaling in IM-resistant cells and abolished the protective effects of mesenchymal stromal cells (MSCs) to CML cells. In addition, the co-treatment significantly reduced Bcr-Abl and beta-catenin transcript levels and induced apoptosis of primary CD34(+) stem/progenitor cells derived from blast crisis (BC)-CML patients, but exhibited minimal toxicity to normal CD34(+) progenitors. Collectively, our data show that combination of chidamide and imatinib synergistically targets tyrosine kinase inhibitor (TKI) -resistant BC-CML cells via inhibition of Bcr-Abl and beta-catenin signaling, suggesting that this combination has the potential for treating TKI-resistant CML and improving clinical outcomes of BC-CML patients.