Liu Man-Yu, Wang Wei-Zhang, Liao Fen-Fang, Wu Qing-Qing, Lin Xiang-Hua, Chen Yong-Hen, Cheng Lin, Jin Xiao-Bao, Zhu Jia-Yong
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P. R. China.
Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, P. R. China.
Cell Biol Int. 2017 Jan;41(1):16-23. doi: 10.1002/cbin.10686. Epub 2016 Nov 16.
Imatinib mesylate (IM) and other BCR-ABL tyrosine kinase inhibitors (TKIs) have improved chronic myeloid leukemia (CML) patient survival markedly but fail to eradicate quiescent CML leukemia stem cells (LSCs). Thus, strategies targeting LSCs are required to induce long-term remission and achieve cure. Here, we investigated the ability of topoisomerase II (Top II) inhibitor etoposide (Eto) to target CML LSCs. Treatment with Eto combined with IM markedly induced apoptosis in primitive CML CD34 CD38 stem cells resistant to eradication by IM alone, but not in normal hematopoietic stem cells, CML and normal mature CD34 cells, and other leukemia and lymphoma cell lines. The interaction of IM and Eto significantly inhibited phosphorylation of PDK1, AKT, GSK3, S6, and ERK proteins; increased the expression of pro-apoptotic gene Bax; and decreased the expression of anti-apoptotic gene c-Myc in CML CD34 cells. Top II inhibitors treatment represents an attractive approach for targeting LSCs in CML patients undergoing TKIs monotherapy.
甲磺酸伊马替尼（IM）和其他BCR-ABL酪氨酸激酶抑制剂（TKIs）显著提高了慢性髓性白血病（CML）患者的生存率，但未能根除静止的CML白血病干细胞（LSCs）。因此，需要靶向LSCs的策略来诱导长期缓解并实现治愈。在此，我们研究了拓扑异构酶II（Top II）抑制剂依托泊苷（Eto）靶向CML LSCs的能力。Eto与IM联合治疗显著诱导了单独使用IM无法根除的原始CML CD34 CD38干细胞凋亡，但对正常造血干细胞、CML和正常成熟CD34细胞以及其他白血病和淋巴瘤细胞系无此作用。IM与Eto的相互作用显著抑制了PDK1、AKT、GSK3、S6和ERK蛋白的磷酸化；增加了促凋亡基因Bax的表达；并降低了CML CD34细胞中抗凋亡基因c-Myc的表达。Top II抑制剂治疗是一种针对接受TKIs单一疗法的CML患者中LSCs的有吸引力的方法。
