The Challenge of Developing Autophagy Inhibition as a Therapeutic Strategy.
The Challenge of Developing Autophagy Inhibition as a Therapeutic Strategy.
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DOI：
10.1158/0008-5472.can-16-0722
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发表时间：
2016-10-01
期刊：
影响因子：
11.2
通讯作者：
Gewirtz DA
中科院分区：
文献类型：
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作者：
Gewirtz DA
癌症化疗药物和电离辐射经常促进自噬的发现为自噬阻断剂与抗肿瘤药物和辐射联合的临床试验提供了基础。推动这些试验的前提是治疗诱导的自噬具有细胞保护作用。因此，抑制自噬预计会使恶性肿瘤对治疗敏感。然而，众所周知，自噬也可能介导抗肿瘤药物的毒性，同时也有证据表明自噬具有非保护性功能。因此，鉴于无法预测化疗或放疗后自噬会采取何种形式，目前正在进行的临床试验可能会产生矛盾或不一致的结果，潜在的后果是自噬抑制可能会因本质上是假阴性结果而被排除在治疗策略之外。对这些试验结果的适当解释需要了解所使用的药物或放射是否促进肿瘤细胞中的细胞保护形式的自噬，以及氯喹或羟氯喹是否实际上抑制自噬。最终，有必要确定那些自噬抑制策略有望改善治疗反应的患者。然而，由于缺乏适当的生物测定或预测标记来表征自噬或在临床上抑制自噬的药理学方法的有效性，目前这是不可行的。
The finding that cancer chemotherapeutic drugs and ionizing radiation often promote autophagy has provided the foundation for clinical trials combining autophagy-blocking agents with antitumor drugs and radiation. The premise driving these trials is that therapy-induced autophagy is cytoprotective; consequently, inhibition of autophagy is anticipated to sensitize malignancies to therapy. However, in it is well-established that autophagy may also mediate the toxicity of antitumor drugs while evidence also exists for a nonprotective function of autophagy. Consequently, given that it cannot be predicted what form autophagy will take upon treatment with chemotherapy or radiation, the current ongoing clinical trials are likely to generate contradictory or inconsistent results, with the potential consequence that autophagy inhibition could be dismissed as therapeutic strategy based on what are essentially false negative outcomes. Appropriate interpretation of the outcomes of these trials would require knowledge as to whether the drugs or radiation utilized promote the cytoprotective form of autophagy in the tumor cells as well as whether the chloroquine or hydroxychloroquine actually inhibited the autophagy. Ultimately, it will be necessary to identify those patients for whom the strategy of autophagy inhibition would be anticipated to improve the response to therapy. However, this is currently not feasible in the absence of appropriate bioassays or predictive markers for characterization of the autophagy or the effectiveness of pharmacological approaches for autophagy inhibition in the clinic.