Nutritionally Available Selenocysteine Derivative Antagonizes Cisplatin-Induced Toxicity in Renal Epithelial Cells through Inhibition of Reactive Oxygen Species-Mediated Signaling Pathways

摘要

Discovery of nutritionally available agents that could antagonize cisplatin-induced nephrotoxicity is of great significance and clinical application potential. 3,3'-Diselenodipropionic acid (DSePA) is a seleno-amino acid derivative that exhibits strong antioxidant activity. Therefore, this study aimed to examine the protective effects of DSePA on cisplatin-induced renal epithelial cells damage as well as the molecular mechanisms. The results revealed that DSePA effectively inhibited cell apoptosis induced by cisplatin through suppressing the caspase activation and poly(ADP-ribose) polymerase cleavage. In addition, DSePA blocked the cisplatin-induced mitochondrial dysfunction, as evidenced by the loss of mitochondrial membrane potential and reduction of mitochondrial mass. The results of western blot analysis showed that DSePA reversed the expression level of Bcl-2 family proteins altered by cisplatin. The cisplatin-activated AKT pathway was also modulated by DSePA. Moreover, these results indicate that DSePA could protect HK-2 cells from cisplatin-induced toxicity in renal epithelial cells by inhibiting intracellular reactive oxygen species-mediated apoptosis while showing an unobvious effect on its anticancer efficacy. Taken together, this study demonstrates that selenocysteine could be further developed as novel nutritionally available agents to antagonize cisplatin-induced nephrotoxicity during cancer therapy.