Cepharanthine hydrochloride induces mitophagy targeting GPR30 in hepatocellular carcinoma (HCC)

Objectives: Cepharanthine exhibits a wide range of therapeutic effects against numerous cancers by virtue of its pleiotropic mechanisms. However, cepharanthine monotherapy has insufficient drug efficacy for cancers in animal models and clinical trials. The mechanism of its limited efficacy is unknown. Methods: We investigated the possible mechanism for the limited drug efficacy of cepharanthine in cancer therapy using both hepatocellular carcinoma (HCC) primary cells and cell lines, in vitro and in mouse xenograft models. Results: We found that cepharanthine hydrochloride (CH), a semi-synthetic derivative of cepharanthine, induced mitophagy independent of mTOR signaling, and played an AMPK-dependent protective role in the cell fate of HCC in vitro and in vivo. Mechanistically, we demonstrated that CH may bind to GPR30 receptor to activate the subsequent signal cascade involving mitochondrial fission, thus facilitating mitophagy. Therefore, we proposed a new therapeutic regimen for HCC involving CH combined with an autophagy inhibitor. This regimen exhibited remarkable anti-cancer effects in HCC xenograft mouse model. Conclusion: These results identify CH as a new mitophagy inducer targeting GPR30 receptor. The combination therapy of CH and an autophagy inhibitor may become a novel strategy for enhancing the anti-tumor potential of cepharanthine in HCC.