Principles and current strategies for targeting autophagy for cancer treatment.
Principles and current strategies for targeting autophagy for cancer treatment.
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DOI：
10.1158/1078-0432.ccr-10-2634
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发表时间：
2011-02-15
期刊：
影响因子：
--
通讯作者：
White E
中科院分区：
文献类型：
--
作者：
Amaravadi RK;Lippincott-Schwartz J;Yin XM;Weiss WA;Takebe N;Timmer W;DiPaola RS;Lotze MT;White E
自噬是一种进化上保守的细胞内自卫机制，其中细胞器和蛋白质被隔离在自噬囊泡（AVs）中，随后通过与溶酶体融合而降解。因此，细胞可以防止受损或不必要成分的毒性积累，同时也可以回收这些成分以维持代谢平衡。增强的自噬是癌细胞面对代谢和治疗应激的一种抵抗机制，揭示了作为癌症治疗靶点的开发机会。我们总结了自噬和癌症领域的最新进展，并以2010年3月在癌症治疗和评估项目（CTEP）早期药物开发会议上发表的结果为基础。在此，我们描述了我们目前对自噬机制核心成分的理解，自噬在肿瘤微环境中的功能相关性，并概述了这些知识如何为自噬抑制剂羟氯喹（HCQ）与化疗、靶向治疗和免疫治疗相结合的临床前研究提供信息。最后，我们描述了正在进行的有关HCQ作为第一代自噬抑制剂的临床试验，以及开发新型、更有效和特异性自噬抑制剂的策略。
Autophagy is an evolutionarily conserved, intracellular self-defense mechanism where organelles and proteins are sequestered into autophagic vesicles (AVs) that are subsequently degraded through fusion with lysosomes. Cells thereby prevent the toxic accumulation of damaged or unnecessary components, but also recycle these components to sustain metabolic homoeostasis. Heightened autophagy is a mechanism of resistance for cancer cells faced with metabolic and therapeutic stress, revealing opportunities for exploitation as a therapeutic target in cancer. We summarize recent developments in the field of autophagy and cancer, and build upon the results presented at the Cancer Therapeutics and Evaluation Program (CTEP) Early Drug Development meeting in March, 2010. Herein, we describe our current understanding of the core components of the autophagy machinery, the functional relevance of autophagy within the tumor microenvironment and outline how this knowledge has informed preclinical investigations combining the autophagy inhibitor hydroxychloroquine (HCQ) with chemotherapy, targeted therapy and immunotherapy. Finally, we describe ongoing clinical trials involving HCQ as a first generation autophagy inhibitor, as well as strategies for the development of novel, more potent and specific inhibitors of autophagy.