期刊
CHEMICO-BIOLOGICAL INTERACTIONS
卷 364, 期 -, 页码 -出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2022.110060
关键词
Epirubicin; (-)-Gossypol; Survivin; Sensitization; Hepatocellular carcinoma
资金
- Natural Science Foundation of Chongqing [cstc2021jcyj-bshX0200]
- Special Fund for Postdoctoral Science Research of Chongqing [2021XM2050]
- National Natural Science Foundation of China [81872024]
In this study, we demonstrated for the first time that (-)-Gsp sensitizes EPI to inhibit cell growth and induce apoptosis in hepatocellular carcinoma cells. (-)-Gsp sensitizes EPI by attenuating the EPI-elevated survivin protein levels. Mechanistic studies showed that (-)-Gsp alleviates survivin protein synthesis by suppressing the AKT-4EBP1/p70S6K-survivin and ERK-4EBP1-survivin pathways.
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.
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