Modulating autophagy for therapeutic benefit
Modulating autophagy for therapeutic benefit
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DOI：
10.4161/auto.4311
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发表时间：
2007-09-01
期刊：
影响因子：
13.3
通讯作者：
Cleveland, John L.
中科院分区：
文献类型：
--
作者：
Carew, Jennifer S.;Nawrocki, Steffan T.;Cleveland, John L.
自噬是一种古老的细胞生存途径，当细胞缺乏营养或暴露于缺氧时，它允许细胞重新获得ATP和生物合成的基本构件，这是肿瘤微环境的标志。该途径涉及形成双膜囊泡，即自噬体，其包裹大量细胞物质和/或细胞器，随后与降解其货物的溶酶体融合。自噬被认为在肿瘤对某些治疗药物的化学抗性中起重要作用，其通常诱导凋亡反应。例如，组蛋白裂解乙酰化酶抑制剂SAHA诱导细胞凋亡和自噬，这表明破坏自噬途径的药物可能会增强其作为治疗剂的功效。我们在伊马替尼难治性慢性粒细胞白血病（CML）模型和伊马替尼耐药的原发性CML细胞中测试了这一概念，这些细胞来自Bcr-Abl突变患者，包括T3 151突变，该突变导致对目前使用的酪氨酸激酶抑制剂的耐药性，并转化为非常差的临床预后。破坏自噬的药物与SAHA协同作用，引起这些难治性肿瘤的凋亡。这些发现支持在化学难治性恶性肿瘤中使用破坏自噬途径的药物。
Autophogy is an ancient cell survival pathway that allows cells to recoup ATP and essential building blocks for biosynthesis when they are starved of nutrients or when they are exposed to hypoxia, which are hallmarks of the tumor microenvironment. This pathway involves the formation of double-membraned vesicles, coined autophagosomes, which envelop bulk cellular material and/or organelles and that subsequently fuse with lysosomes that degrade their cargo. Autophagy has been suggested to play important roles in chemoresistance of cancer to some therapeutic agents, which typically induce an apoptotic response. For example, the histone cleacetylase inhibitor SAHA induces both apoptosis and autophagy, suggesting that agents that disrupt the autophagy pathway might augment its efficacy as a therapeutic agent. We tested this notion in a model of Imatinib-refractory chronic myelogenous leukemia (CML) and in imatinib-resistant primary CML cells from patients bearing mutations in Bcr-Abl, including the T3 151 mutation that causes resistance to currently utilized tyrosine kinase inhibitors and translates into a very poor clinical prognosis. Agents that disrupt autophogy were shown to synergize with SAHA in provoking apoptotic death of these refractory tumors. These findings support the use of agents that disrupt the autophagy pathway in settings of chemorefractory malignancies.