Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment.
Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment.
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DOI：
10.1186/s13045-017-0436-9
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发表时间：
2017-03-09
影响因子：
28.5
通讯作者：
Yoshida GJ
中科院分区：
文献类型：
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作者：
Yoshida GJ
2016年诺贝尔生理学或医学奖授予发现自噬的研究人员，自噬是一种进化保守的分解代谢过程，它降解溶酶体中的细胞质成分和细胞器。自噬在正常组织稳态和肿瘤发展中起着至关重要的作用，并且是癌细胞有效适应以低营养条件为特征的不利肿瘤微环境所必需的。这种蛋白质降解过程导致氨基酸再循环，这为细胞存活和增殖提供了足够的氨基酸底物。自噬在癌细胞中由于PI 3 K/Akt/mTOR信号通路的失调而被组成性激活，这使得它们能够适应低营养微环境并在转移前的小生境中表现出稳健的增殖。这就是为什么仅仅用mTOR抑制剂激活自噬往往是徒劳的。相反，自噬-溶酶体通量的紊乱导致内质网（ER）应激和未折叠蛋白反应（UPR），其最终导致肿瘤组织中凋亡细胞死亡增加。越来越多的证据表明，自噬与程序性细胞死亡有着密切的关系，而不受控制的自噬本身往往会导致肿瘤细胞的自噬性细胞死亡。自噬性细胞死亡最初被定义为伴随细胞质大规模自噬性空泡化的细胞死亡。然而，自噬对癌细胞来说是一把“双刃剑”，它既可以促进也可以抑制肿瘤微环境中的生存和增殖。此外，药物重新定位的几项研究表明，用于治疗癌症以外的疾病的“常规”药剂可以通过激活/抑制自噬而具有抗肿瘤治疗效果。由于与抗癌药物开发相关的不断增加的失败率和高成本，这种治疗开发策略引起了越来越多的关注，因为这些药物的安全性是众所周知的。抗疟药如青蒿素和疾病缓解抗风湿药（DMARD）是影响治疗用途的自噬调节的药物重新定位的典型例子。这篇综述文章的重点是一些新的治疗策略的最新进展，靶向自噬，以期治疗/预防恶性肿瘤。
The 2016 Nobel Prize in Physiology or Medicine was awarded to the researcher that discovered autophagy, which is an evolutionally conserved catabolic process which degrades cytoplasmic constituents and organelles in the lysosome. Autophagy plays a crucial role in both normal tissue homeostasis and tumor development and is necessary for cancer cells to adapt efficiently to an unfavorable tumor microenvironment characterized by hypo-nutrient conditions. This protein degradation process leads to amino acid recycling, which provides sufficient amino acid substrates for cellular survival and proliferation. Autophagy is constitutively activated in cancer cells due to the deregulation of PI3K/Akt/mTOR signaling pathway, which enables them to adapt to hypo-nutrient microenvironment and exhibit the robust proliferation at the pre-metastatic niche. That is why just the activation of autophagy with mTOR inhibitor often fails in vain. In contrast, disturbance of autophagy–lysosome flux leads to endoplasmic reticulum (ER) stress and an unfolded protein response (UPR), which finally leads to increased apoptotic cell death in the tumor tissue. Accumulating evidence suggests that autophagy has a close relationship with programmed cell death, while uncontrolled autophagy itself often induces autophagic cell death in tumor cells. Autophagic cell death was originally defined as cell death accompanied by large-scale autophagic vacuolization of the cytoplasm. However, autophagy is a “double-edged sword” for cancer cells as it can either promote or suppress the survival and proliferation in the tumor microenvironment. Furthermore, several studies of drug re-positioning suggest that “conventional” agents used to treat diseases other than cancer can have antitumor therapeutic effects by activating/suppressing autophagy. Because of ever increasing failure rates and high cost associated with anticancer drug development, this therapeutic development strategy has attracted increasing attention because the safety profiles of these medicines are well known. Antimalarial agents such as artemisinin and disease-modifying antirheumatic drug (DMARD) are the typical examples of drug re-positioning which affect the autophagy regulation for the therapeutic use. This review article focuses on recent advances in some of the novel therapeutic strategies that target autophagy with a view to treating/preventing malignant neoplasms.
影响因子：
82.9
作者：
Weinberg R;Fisher DE;Rich J
通讯作者：
Rich J