雷公藤醇
粒体自噬
程序性细胞死亡
细胞凋亡
癌症研究
自噬
坏死性下垂
基因敲除
化学
药理学
生物
生物化学
作者
Ming Liu,Yumei Fan,Danyu Li,Bihui Han,Yanxiu Meng,Fei Chen,Tianchan Liu,Zhiyuan Song,Yu Han,Liying Huang,Yan-Zhong Chang,Pengxiu Cao,Akira Nakai,Ke Tan
标识
DOI:10.1002/1878-0261.12936
摘要
Despite recent progress in non-small-cell lung cancer (NSCLC) treatment, treatment outcomes remain poor, mainly because of treatment resistance or toxicity. Erastin is a ferroptosis inducer that has shown promising cytotoxic effects in various types of cancers, including NSCLC. Celastrol is a triterpene extracted from the Tripterygium wilfordii that exhibits potential anticancer activity. However, the side effects of celastrol are severe and limit its clinical application. Combination therapy is a promising strategy to overcome the compensatory mechanisms and unwanted off-target effects. In the present study, we found that erastin synergized with celastrol to induce cell death at nontoxic concentrations. The combined treatment with celastrol and erastin significantly increased reactive oxygen species (ROS) generation, disrupted mitochondrial membrane potential, and promoted mitochondrial fission. Furthermore, cotreatment with erastin and celastrol initiated ATG5/ATG7-dependent autophagy, PINK1/Parkin-dependent mitophagy, and the expression of heat shock proteins (HSPs) in an HSF1-dependent manner. HSF1 knockdown further enhanced cell death in vitro and inhibited tumor growth in vivo. Our findings indicate that the combination of celastrol with erastin may represent a novel therapeutic regimen for patients with NSCLC and warrants further clinical evaluation.
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