(−)-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.