(-)-Gossypol enhances the anticancer activity of epirubicin via downregulating survivin in hepatocellular carcinoma

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.