Targeting the Bcl-2-regulated apoptosis pathway by BH3 mimetics: a breakthrough in anticancer therapy?
Targeting the Bcl-2-regulated apoptosis pathway by BH3 mimetics: a breakthrough in anticancer therapy?
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DOI：
10.1038/cdd.2008.37
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发表时间：
2008-06
影响因子：
12.4
通讯作者：
Villunger A
中科院分区：
文献类型：
--
作者：
Labi V;Grespi F;Baumgartner F;Villunger A
通过小分子药物直接激活Bcl-2调节的细胞凋亡途径诱导肿瘤细胞凋亡，有望克服目前抗癌疗法的缺点。这种新的治疗概念建立在对Bcl-2样分子如何维持线粒体完整性以及促凋亡BH 3蛋白如何导致其破坏的新见解的基础上。释放肿瘤细胞中仅有BH 3的蛋白的促凋亡潜力的手段，或通过直接阻断Bcl-2样促存活分子与Bax和/或巴克的可能相互作用而绕过对仅有BH 3的蛋白的需要的手段，构成了用于设计新的抗癌疗法的令人感兴趣的选择。对于这些新的抗癌策略的优化和临床实施，需要详细了解单个BH 3-only蛋白在健康细胞和肿瘤抑制期间的细胞死亡信号传导中的作用。在这篇综述中，我们将触及的最新发现BH 3-唯一的蛋白质功能，并试图定义所谓的“BH 3模拟物，”一类新型的抗癌药物，能够促进肿瘤细胞凋亡的分子特性，无论其p53或Bcl-2的状态。
Induction of apoptosis in tumor cells by direct activation of the Bcl-2-regulated apoptosis pathway by small molecule drugs carries high hopes to overcome the shortcomings of current anticancer therapies. This novel therapy concept builds on emerging insights into how Bcl-2-like molecules maintain mitochondrial integrity and how pro-apoptotic BH3-only proteins lead to its disruption. Means to unleash the pro-apoptotic potential of BH3-only proteins in tumor cells, or to bypass the need for BH3-only proteins by directly blocking possible interactions of Bcl-2-like pro-survival molecules with Bax and/or Bak, constitute interesting options for the design of novel anticancer therapies. For the optimization and clinical implementation of these novel anticancer strategies, a detailed understanding of the role of individual BH3-only proteins in cell death signaling in healthy cells and during tumor suppression is required. In this review, we will touch on the latest findings on BH3-only protein function and attempts to define the molecular properties of the so-called ‘BH3 mimetics,’ a novel class of anticancer agents, able to prompt apoptosis in tumor cells, regardless of their p53 or Bcl-2 status.