JS-K induces reactive oxygen species-dependent anti-cancer effects by targeting mitochondria respiratory chain complexes in gastric cancer

As a nitric oxide (NO) donor prodrug, JS-K inhibits Cancer cell proliferation, induces the differentiation of human leukaemia cells, and triggers apoptotic cell death in various Cancer models. However, the anti-cancer effect of JS-K in gastric Cancer has not been reported. In this study, we found that JS-K inhibited the proliferation of gastric Cancer cells in vitro and in vivo and triggered mitochondrial Apoptosis. Moreover, JS-K induced a significant accumulation of Reactive Oxygen Species (ROS), and the clearance of ROS by antioxidant reagents reversed JS-K-induced toxicity in gastric Cancer cells and subcutaneous xenografts. Although JS-K triggered significant NO release, NO scavenging had no effect on JS-K-induced toxicity in vivo and in vitro. Therefore, ROS, but not NO, mediated the anti-cancer effects of JS-K in gastric Cancer. We also explored the potential mechanism of JS-K-induced ROS accumulation and found that JS-K significantly down-regulated the core proteins of mitochondria respiratory chain (MRC) complex I and IV, resulting in the reduction of MRC complex I and IV activity and the subsequent ROS production. Moreover, JS-K inhibited the expression of antioxidant enzymes, including copper-zinc-containing superoxide dismutase (SOD1) and catalase, which contributed to the decrease of antioxidant enzymes activity and the subsequent inhibition of ROS clearance. Therefore, JS-K may target MRC complex I and IV and antioxidant enzymes to exert ROS-dependent anti-cancer function, leading to the potential usage of JS-K in the prevention and treatment of gastric Cancer.