Simultaneous targeting of MCL1 and ABCB1 as a novel strategy to overcome drug resistance in human leukaemia
Simultaneous targeting of MCL1 and ABCB1 as a novel strategy to overcome drug resistance in human leukaemia
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同时靶向 MCL1 和 ABCB1 作为克服人类白血病耐药性的新策略
DOI：
10.1111/j.1365-2141.2009.07678.x
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发表时间：
2009-06-01
影响因子：
6.5
通讯作者：
Ji, Chunyan
中科院分区：
文献类型：
--
作者：
Ji, Min;Li, Jie;Ji, Chunyan
耐药性是白血病化疗成功的主要障碍。虽然ABCB1(Mdr1)的过度表达是耐药的重要机制，但ABCB1的调控显示出不满意的临床结果。最近的研究表明，MCL1在许多血液系统和实体肿瘤中表达上调。目前的研究发现，初诊或复发/难治性白血病患者的MCL1水平高于完全缓解患者。我们证明，MCL1的过表达降低了人白血病细胞系对细胞毒药物的敏感性，并抑制了药物诱导的细胞凋亡。通过RNA干扰特异性下调MCL1，使多药耐药白血病细胞对化疗敏感，并诱导细胞凋亡。我们的研究还表明，MCL1和ABCB1通过不同的机制介导耐药，MCL1和ABCB1的缺失在逆转耐药和促进药物诱导的细胞凋亡方面显示出相加的作用。因此，本研究证实了MCL1在耐药和细胞凋亡中的重要作用。同时靶向MCL1和ABCB1有望成为克服白血病耐药的新途径。
Drug resistance is a major obstacle to chemotherapy success in leukaemia. Although ABCB1 (MDR1) overexpression represents a critical mechanism of drug resistance, modulation of ABCB1 shows unsatisfactory clinical outcome. Recent studies showed that MCL1 was upregulated in numerous haematological and solid tumour malignancies. The present study found that patients with newly diagnosed or relapsed/refractory leukaemia expressed higher MCL1 levels than patients that were in complete remission. We demonstrated that overexpression of MCL1 decreased sensitivity of human leukaemia cell lines to cytotoxic drugs and inhibited drug‐induced apoptosis. Specific downregulation of MCL1 via RNA interference sensitized multidrug resistant leukaemia cells towards chemotherapy and induced apoptosis. Our study also demonstrated that MCL1 and ABCB1 mediated drug resistance through different mechanisms and the depletion of both MCL1 and ABCB1 showed an additive effect in reversing drug resistance and promoting drug‐induced apoptosis. Thus, this study documented an important role of MCL1 in drug resistance and apoptosis. Simultaneous targeting of MCL1 and ABCB1 could be a novel approach to overcome drug resistance in leukaemia.