The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular carcinoma [corrected] cells

Apogossypolone (ApoG2), a novel derivative of gossypol, exhibits superior antitumor activity in Bcl-2 transgenic mice, and induces Autophagy in several Cancer cells. However, the detailed mechanisms are not well known. In the present study, we showed that ApoG2 induced Autophagy through Beclin-1- and Reactive Oxygen Species (ROS)-dependent manners in human hepatocellular carcinoma (HCC) cells. Incubating the HCC cell with ApoG2 abrogated the interaction of Beclin-1 and Bcl-2/xL, stimulated ROS generation, increased phosphorylation of ERK and JNK, and HMGB1 translocation from the nucleus to cytoplasm while suppressing mTOR. Moreover, inhibition of the ROS-mediated Autophagy by antioxidant N-acetyl-cysteine (NAC) potentiates ApoG2-induced Apoptosis and cell killing. Our results show that ApoG2 induced protective Autophagy in HCC cells, partly due to ROS generation, suggesting that antioxidant may serve as a potential chemosensitizer to enhance Cancer cell death through blocking ApoG2-stimulated Autophagy. Our novel insights may facilitate the rational design of clinical trials for Bcl-2-targeted Cancer therapy.