Targeting cell death signalling in cancer: minimising 'Collateral damage'.
Targeting cell death signalling in cancer: minimising 'Collateral damage'.
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DOI：
10.1038/bjc.2016.111
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发表时间：
2016-06-28
影响因子：
8.8
通讯作者：
MacFarlane M
中科院分区：
文献类型：
--
作者：
Fox JL;MacFarlane M
靶向细胞凋亡用于治疗癌症已成为越来越有吸引力的策略，开发中的药剂通过TRAIL信号传导触发外源性细胞凋亡，或阻止BCL-2蛋白或细胞凋亡抑制剂（IAP）蛋白的抗细胞凋亡活性。虽然逃避细胞凋亡是癌症的标志之一，但许多癌症具有完整的细胞凋亡信号通路，如果畅通，可以有效地杀死癌细胞。然而，越来越清楚的是，如果没有对凋亡和非凋亡信号传导以及调节这些途径的关键蛋白质的详细了解，可能会出现与其调节相关的剂量限制性毒性和不良反应。在这里，我们回顾了直接针对抗癌治疗的主要凋亡途径及其调制的不可预见的后果。此外，我们强调了深入了解作为抗癌药物靶点的这些蛋白质的凋亡和非凋亡功能的重要性，并概述了一些使癌细胞对凋亡敏感的新方法，从而提高了现有疗法与新型靶向药物联合使用时的疗效。
Targeting apoptosis for the treatment of cancer has become an increasingly attractive strategy, with agents in development to trigger extrinsic apoptosis via TRAIL signalling, or to prevent the anti-apoptotic activity of BCL-2 proteins or inhibitor of apoptosis (IAP) proteins. Although the evasion of apoptosis is one of the hallmarks of cancer, many cancers have intact apoptotic signalling pathways, which if unblocked could efficiently kill cancerous cells. However, it is becoming increasing clear that without a detailed understanding of both apoptotic and non-apoptotic signalling, and the key proteins that regulate these pathways, there can be dose-limiting toxicity and adverse effects associated with their modulation. Here we review the main apoptotic pathways directly targeted for anti-cancer therapy and the unforeseen consequences of their modulation. Furthermore, we highlight the importance of an in-depth mechanistic understanding of both the apoptotic and non-apoptotic functions of those proteins under investigation as anti-cancer drug targets and outline some novel approaches to sensitise cancer cells to apoptosis, thereby improving the efficacy of existing therapies when used in combination with novel targeted agents.