Abstract
The small molecule multi-kinase inhibitor sorafenib has become the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC) and renal cell carcinoma. Similar to other kinase inhibitors, drug resistance hinders its clinical use; thus, combination therapy to improve sorafenib sensitivity is a promising approach. The present study shows for the first time that the combination of sorafenib and wogonin exerts a significant potentiation of cytotoxicity in a number of human HCC cell lines in a dose-dependent manner. Enhanced cell death was due to potentiation of apoptosis, which was demonstrated by increased apoptotic cell populations, caspase activation and suppression of cell death by the pan-caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl. Sorafenib induced autophagy activation, which was shown by autophagic flux. Suppression of autophagy with the autophagy inhibitors chloroquine or 3-methyladenine significantly enhanced cytotoxicity, suggesting that sorafenib-induced autophagy is cytoprotective. Notably, wogonin effectively inhibited sorafenib-induced autophagy. Altogether, our results indicate that the combination of wogonin and sorafenib effectively kills human HCC cells. This occurs, at least in part, through autophagy inhibition, which potentiates apoptosis. Thus, wogonin could be an ideal candidate for increasing sorafenibs activity in HCC therapy, which warrants further investigation in vivo.