The BCL-2 arbiters of apoptosis and their growing role as cancer targets.
The BCL-2 arbiters of apoptosis and their growing role as cancer targets.
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DOI：
10.1038/cdd.2017.161
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发表时间：
2018-01
影响因子：
12.4
通讯作者：
Cory S
中科院分区：
文献类型：
--
作者：
Adams JM;Cory S
受损的细胞凋亡在癌症发展中起着核心作用，并限制了常规细胞毒性疗法的功效。对BCL-2蛋白家族的对立派别如何开启细胞凋亡及其结构的深入了解，推动了一类新的癌症药物的开发，这些药物通过模拟其天然抑制剂BH 3-only蛋白质来靶向各种促生存成员。这些“BH 3模拟物”药物似乎注定要成为对抗癌症的强大新武器。Venetoclax/ABT-199（BCL-2的特异性抑制剂）的成功临床试验已导致其批准用于难治性慢性淋巴细胞白血病，并导致正在进行的其他恶性肿瘤试验的分数。此外，针对其他BCL-2促生存成员（特别是MCL-1）的BH 3模拟物的临床前研究令人鼓舞，为对维奈托克耐药的癌症提供了希望。本文概述了BCL-2家族对癌症发展和治疗的影响，描述了家族成员之间的相互作用如何触发细胞凋亡，并讨论了BH 3模拟药物推进癌症治疗的潜力。
Impaired apoptosis plays a central role in cancer development and limits the efficacy of conventional cytotoxic therapies. Deepening understanding of how opposing factions of the BCL-2 protein family switch on apoptosis and of their structures has driven development of a new class of cancer drugs that targets various pro-survival members by mimicking their natural inhibitors, the BH3-only proteins. These ‘BH3 mimetic’ drugs seem destined to become powerful new weapons in the arsenal against cancer. Successful clinical trials of venetoclax/ABT-199, a specific inhibitor of BCL-2, have led to its approval for a refractory form of chronic lymphocytic leukaemia and to scores of on-going trials for other malignancies. Furthermore, encouraging preclinical studies of BH3 mimetics that target other BCL-2 pro-survival members, particularly MCL-1, offer promise for cancers resistant to venetoclax. This review sketches the impact of the BCL-2 family on cancer development and therapy, describes how interactions of family members trigger apoptosis and discusses the potential of BH3 mimetic drugs to advance cancer therapy.