Capsaicin and sorafenib combination treatment exerts synergistic anti-hepatocellular carcinoma activity by suppressing EGFR and PI3K/Akt/mTOR signaling

摘要

Capsaicin (8-methyl N-vanillyl-6 nonenamide) is a natural plant extract that has antitumor properties and induces apoptosis and autophagy in various types of malignancies, including hepatocellular carcinoma (HCC). Sorafenib is a multi-kinase inhibitor that improves the survival of patients with advanced HCC. In the present study, capsaicin and sorafenib were found to inhibit the growth of LM3, Hep3B and HuH7 cells. In addition, the combination of capsaicin and sorafenib exerted a synergistic inhibitory effect on HCC cell growth. In LM3 cells, capsaicin and sorafenib combination treatment achieved a markedly stronger induction of apoptosis by increasing caspase-3, Bax and poly(ADP-ribose) polymerase activity and inhibiting Bcl-2, and induction of autophagy by upregulating the levels of beclin-1 and LC3A/B II, enhancing P62 degradation. The combination of capsaicin and sorafenib also inhibited cell invasion and metastasis via upregulation of E-cadherin and downregulation of N-cadherin, vimentin, matrix metalloproteinase (MMP)2 and MMP9. Additional studies suggested an association between the abovementioned anticancer activities and inhibition of the epidermal growth factor receptor/phosphoinositide 3 kinase/Akt/mammalian target of rapamycin pathway. Taken together, these data confirm that capsaicin and sorafenib combination treatment inhibits the growth, invasion and metastasis of HCC cells and induces autophagy in a synergistic manner, supporting its potential as a therapeutic option for HCC.