Alkannin induces cytotoxic autophagy and apoptosis by promoting ROS-mediated mitochondrial dysfunction and activation of JNK pathway

Naphthoquinone derivatives and metabolites are widely dispersed molecules in nature. Alkannin, a natural naphthoquinone compound, induces excellent cytotoxicity in cancer cells. However, the detailed mechanism by which alkannin inhibits cancer cell survival remains unclear. In the present study, we isolated alkannin from Arnebia euchroma and found that alkannin induced cytotoxic autophagy and apoptosis in many types of cancer cells in a dose-dependent manner. Alkannin treatment resulted in elevated accumulation of intracellular reactive oxygen species (ROS), leading to mitochondrial membrane potential loss, oxidative damage and JNK and p38 MAPK pathway activation. Notably, we found an antagonistic pattern of p38 MAPK and JNK signaling in the regulation of alkannin-mediated apoptosis and autophagy. Antioxidant NAC effectively attenuated alkannin-induced cytotoxicity and activation of downstream signaling pathways. Moreover, alkannin enhanced the sensitivity of cancer cells to chemotherapeutic agents. In summary, our study highlights the significant broad-spectrum antitumor effects of alkannin and reveals an important mechanism by which alkannin induces cytotoxic autophagy and apoptosis by promoting ROS-mediated mitochondrial dysfunction and activation of the JNK pathway.