(-)-Gossypol enhances the anticancer activity of epirubicin via downregulating survivin in hepatocellular carcinoma
(-)-Gossypol enhances the anticancer activity of epirubicin via downregulating survivin in hepatocellular carcinoma
复制标题
()-棉酚通过下调肝细胞癌中的生存素增强表柔比星的抗癌活性
DOI：
10.1016/j.cbi.2022.110060
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发表时间：
2022-08-03
影响因子：
5.1
通讯作者：
He, Fengtian
中科院分区：
文献类型：
--
作者：
Jiang, Wenbin;Wang, Wan;He, Fengtian
以肾上腺素（EPI）为基础的肝动脉化疗栓塞是治疗晚期肝细胞癌（HCC）的有效方法。然而，EPI诱导的Survivin表达限制了其在HCC中的肿瘤杀伤潜力。有趣的是，（-）-棉酚（（-）-Gsp），一种男性避孕药，抑制各种恶性肿瘤。更重要的是，（-）-Gsp还有望增强化疗在许多癌症类型中的抗肿瘤作用。在本研究中，我们首次证实了（-）-Gsp致敏的EPI在体外抑制肝癌细胞生长并诱导其凋亡。此外，（-）-Gsp通过减弱EPI升高的Survivin蛋白水平而致敏EPI。EPI通过促进翻译起始而促进survivin蛋白合成，而（-）-Gsp主要通过抑制AKT-4 EBP 1/p70 S6 K-survivin和ERK-4 EBP 1-survivin通路而抑制EPI的翻译起始。在裸鼠中的HCC异种移植物实验也显示（-）-Gsp处理与EPI协同作用以抑制异种移植物肿瘤生长。总体而言，我们的概念验证结果可能为基于EPI和（-）-Gsp组合的HCC治疗新策略铺平道路。
Epirubicin (EPI)-based transarterial chemoembolization is an effective therapy for advanced hepatocellular carcinoma (HCC). However, EPI-induced survivin expression limits its tumor-killing potential in HCC. Interestingly, (-)-gossypol ((-)-Gsp), a male contraceptive, suppresses various malignancies. More importantly, (-)-Gsp also holds promise for enhancing the antitumor effects of chemotherapy in numerous cancer types. In the present study, we demonstrated for the first time that (-)-Gsp-sensitized EPI inhibited cell growth and induced apoptosis of HCC cells in vitro. Furthermore, (-)-Gsp sensitized EPI by attenuating the EPI-elevated survivin protein levels. Mechanistic studies showed that EPI stimulated survivin protein synthesis by promoting translation initiation, which was alleviated by (-)-Gsp mainly through suppressing the AKT-4EBP1/p70S6K-survivin and ERK-4EBP1-survivin pathways. HCC xenograft experiments in nude mice also showed that (-)-Gsp treatment acted synergistically with EPI to repress xenograft tumor growth. Overall, our proof-of-concept results may pave the way for novel strategies for the treatment of HCC based on the combination of EPI and (-)-Gsp.