Sabutoclax, pan-active BCL-2 protein family antagonist, overcomes drug resistance and eliminates cancer stem cells in breast cancer
Sabutoclax, pan-active BCL-2 protein family antagonist, overcomes drug resistance and eliminates cancer stem cells in breast cancer
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Sabutoclax，泛活性 BCL-2 蛋白家族拮抗剂，克服耐药性并消除乳腺癌中的癌症干细胞
DOI：
10.1016/j.canlet.2018.02.036
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Zhang, Jin
中科院分区：
文献类型：
--
作者：
Hu, Yunhui;Yague, Ernesto;Zhang, Jin
BCL-2蛋白家族的错误调控提供了抵抗细胞毒性抗癌药物的生存信号，并且经常在耐药细胞中发现。耐药表型也与癌症干细胞样（CSC）特征的增强有关。因此，抑制抗凋亡BCL-2家族蛋白已被提出作为一种可能的抗肿瘤策略，目前BCL-2抑制剂正在白血病、淋巴瘤或非小细胞肺癌患者的临床研究中。然而，BCL-2抑制剂对耐药乳腺癌的作用尚未阐明。在本研究中，评估了sabutoclax（一种泛活性BCL-2蛋白家族拮抗剂）对两种化疗耐药乳腺癌细胞系的影响。我们发现sabutoclax在体内和体外对化疗耐药的乳腺癌细胞都有明显的细胞毒活性。化疗药物与sabutoclax联用时，具有较强的协同抗增殖作用。Sabutoclax可阻断BCL-2、MCL-1、BCL-xL和BFL-1，进而激活caspase-3/7和caspase-9，调节Bax、Bim、PUMA和survivin的表达。此外，sabutoclax通过下调IL-6/STAT3信号通路，有效地消除了CSC亚群，减少了耐药细胞的球形形成。在一个由9个乳腺肿瘤组成的小组中也观察到类似的效果。我们的研究结果表明，sabutoclax通过抑制几种抗凋亡的BCL-2家族蛋白介导的凋亡再激活部分克服了乳腺癌细胞的耐药表型，并通过消除lL-6/STAT3途径消除了CSCs。这为探索化疗无反应的乳腺癌患者单独或联合使用沙布托劳的治疗策略提供了强有力的理论依据。(C) 2018 Elsevier B.V.版权所有
Misregulation of BCL-2 family of proteins renders a survival signal to withstand cytotoxic anticancer drugs and is often found in drug resistant cells. The drug resistance phenotype is also associated with an enhancement of cancer stem cell-like (CSC) characteristics. Thus, inhibition of anti-apoptotic BCL-2 family proteins has been proposed as a possible antineoplastic strategy, and BCL-2 inhibitors are currently being clinically trailed in patients with leukemia, lymphoma or non-small cell lung cancer. However, the effects of BCL-2 inhibitors on drug resistant breast cancer have not yet been elucidated. In the present study, the effect of sabutoclax, a pan-active BCL-2 protein family antagonist, on two chemoresistant breast cancer cell lines was assessed. We found that sabutoclax showed a significant cytotoxic activity on chemoresistant breast cancer cells both in vitro and in vivo. When chemotherapeutic agents were combined with sabutoclax, strong synergistic antiproliferative effects were observed. Sabutoclax induced the blockage of BCL-2, MCL-1, BCL-xL and BFL-1, which in turn led to caspase-3/7 and caspase-9 activation and modulation of Bax, Bim, PUMA and survivin expression. Furthermore, sabutoclax effectively eliminated the CSC subpopulation and reduced sphere formation of drug-resistant cells through down-regulation of the IL-6/STAT3 signaling pathway. A similar effect was observed in a small panel of nine breast tumors ex vivo. Our findings indicate that sabutoclax partially overcomes the drug resistance phenotype of breast cancer cells by reactivation of apoptosis, mediated by the inhibition of several anti-apoptotic BCL-2 family proteins, and eliminates CSCs by abolition of the lL-6/STAT3 pathway. This offers a strong rationale to explore the therapeutic strategy of using sabutoclax alone or in combination for chemotherapy-nonresponsive breast cancer patients. (C) 2018 Elsevier B.V. All rights reserved.