A nitric oxide-releasing prodrug promotes apoptosis in human renal carcinoma cells: Involvement of reactive oxygen species

Background - JS-K is a nitric oxide (NO)-releasing pro-drug of the O-2-arylated diazeniumdiolate group that shows pronounced cytotoxicity and antitumor properties in numerous cancer models, including in vitro as well as in vivo. Reactive oxygen species (ROS) induce carcinogenesis by altering the redox status, causing increment in vulnerability to oxidative stress. Material and methods - To determine the effect of JS-K, a glutathione S-transferase (GST)-activated NO-donor prodrug, on the induction of ROS accumulation, proliferation, and apoptosis in human renal carcinoma cells, we measured the changes of cell proliferation, apoptosis, ROS growth, and initiation of the mitochondrial signaling pathway before and after JS-K treatment. Results - In vitro, dose-and time-dependent development of renal carcinoma cells were controlled for JS-K, and JS-K also triggered ROS aggregation and cell apoptosis. Treatment with JS-K induces the levels of pro-apoptotic proteins (Bak and Bax) and decrease the number of anti-apoptotic protein (Bcl-2). In fact, JS-K-induced apoptosis was reversed by the antioxidant N-acetylcysteine, and oxidized glutathione, a pro-oxidant, improved JS-K-induced apoptosis. Finally, we demonstrated that in renal carcinoma cells, JS-K improved the chemosensitivity of doxorubicin. Conclusion - Our data indicate that JS-K-released NO induce apoptosis of renal carcinoma cells by increasing ROS levels.