The autophagy inhibitor chloroquine targets cancer stem cells in triple negative breast cancer by inducing mitochondrial damage and impairing DNA break repair.
The autophagy inhibitor chloroquine targets cancer stem cells in triple negative breast cancer by inducing mitochondrial damage and impairing DNA break repair.
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DOI：
10.1016/j.canlet.2016.04.002
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发表时间：
2016-07-01
期刊：
影响因子：
9.7
通讯作者：
Chang JC
中科院分区：
文献类型：
--
作者：
Liang DH;Choi DS;Ensor JE;Kaipparettu BA;Bass BL;Chang JC
三阴性乳腺癌（TNBC）的特征是大量的耐药乳腺癌干细胞（CSC），其预后比其他类型的乳腺癌更差。尽管其具有侵略性，但对于TNBC不存在有效的靶向治疗。在这里，我们证明了CQ通过自噬抑制、线粒体结构损伤和双链DNA断裂修复损伤有效地靶向CSC。电子显微镜显示CQ诱导的线粒体嵴损伤，导致线粒体膜去极化，细胞色素c氧化酶的活性显著降低，超氧化物和双链DNA断裂的积累。CQ有效地降低了TNBC细胞在体外和TNBC异种移植模型中转移的能力。当与卡铂联合给药时，CQ有效抑制卡铂诱导的自噬。这种联合治疗显著减少了CSC亚群中DNA修复蛋白的表达，导致卡铂耐药BRCA1野生型TNBC原位异种移植物中肿瘤生长减少。由于TNBC的高治疗失败率归因于CSC的富集，CQ（具有抗CSC作用的自噬抑制剂）可能是当前使用卡铂的TNBC化疗方案的有效辅助。
Triple negative breast cancer (TNBC), characterized by an abundance of treatment-resistant breast cancer stem cells (CSCs), has a poorer prognosis than other types of breast cancers. Despite its aggressiveness, no effective targeted therapy exists for TNBC. Here, we demonstrate that CQ effectively targets CSCs via autophagy inhibition, mitochondrial structural damage, and impairment of double-stranded DNA break repair. Electron microscopy demonstrates CQ-induced mitochondrial cristae damage, which leads to mitochondrial membrane depolarization with a significant reduction in the activity of cytochrome c oxidase and accumulation of superoxide and double-stranded DNA breaks. CQ effectively diminishes the TNBC cells’ ability to metastasize in vitro and in a TNBC xenograft model. When administered in combination with carboplatin, CQ effectively inhibits carboplatin-induced autophagy. This combination treatment significantly diminishes the expression of DNA repair proteins in CSC subpopulations, resulting in tumor growth reduction in carboplatin-resistant BRCA1 wild-type TNBC orthotopic xenografts. As TNBC’s high treatment failure rate has been attributed to enrichment of CSCs, CQ, an autophagy inhibitor with anti-CSC effects, may be an effective adjunct to current TNBC chemotherapy regimens with carboplatin.