Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Biomed Pharmacother. 2020 Sep;129:110390. doi: 10.1016/j.biopha.2020.110390. Epub 2020 Jun 17.
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, associated with a marked reduction of Bcr-Abl kinase activity and acetyl-histone H3 expression. The combination treatment markedly inhibited constitutive activity of β-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 β-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 β-catenin signaling, suggesting that this combination has the potential for treating TKI-resistant CML and improving clinical outcomes of BC-CML patients.
西达本胺是一种新型选择性组蛋白去乙酰化酶抑制剂（HDACI），在血液系统恶性肿瘤中具有有前景的活性，但在慢性髓系白血病（CML）中的作用尚未得到充分阐明。在这项研究中，我们首先证明西达本胺单独抑制 CML 细胞增殖，诱导细胞凋亡和细胞周期停滞。此外，西达本胺与伊马替尼（IM）联合在 CML 细胞系 KBM5 以及 IM 耐药的 CML 细胞 KBM5 中诱导协同致死作用，同时显著降低 Bcr-Abl 激酶活性和乙酰化组蛋白 H3 的表达。联合治疗显著抑制了 IM 耐药细胞中β-catenin 信号的组成性活性，并消除了间充质基质细胞（MSCs）对 CML 细胞的保护作用。此外，该联合治疗还显著降低了初发急变期（BC）CML 患者来源的 CD34 干细胞/祖细胞中的 Bcr-Abl 和 β-catenin 转录水平，并诱导其凋亡，但对正常 CD34 祖细胞的毒性最小。总的来说，我们的数据表明，西达本胺与伊马替尼联合通过抑制 Bcr-Abl 和 β-catenin 信号协同靶向 TKI 耐药的 BC-CML 细胞，提示该联合治疗具有治疗 TKI 耐药 CML 和改善 BC-CML 患者临床结局的潜力。
