Renal protective effect of polysulfide in cisplatin-induced nephrotoxicity

Cisplatin is a major chemotherapeutic drug for solid tumors whereas it may lead to severe nephrotoxicity. Despite decades of efforts, effective therapies remain largely lacking for this disease. In the current research, we investigated the therapeutic effect of hydrogen polysulfide, a novel hydrogen sulfide (H₂S) derived signaling molecule, in cisplatin nephrotoxicity and the mechanisms involved. Our results showed that polysulfide donor Na₂S₄ ameliorated cisplatin-caused renal toxicity in vitro and in vivo through suppressing intracellular reactive oxygen species (ROS) generation and downstream mitogen-activated protein kinases (MAPKs) activation. Additionally, polysulfide may inhibit ROS production by simultaneously lessening the activation of NADPH oxidase and inducing nucleus translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in RPT cells. Interestingly, polysulfide possesses anti-cancer activity and is able to add on more anti-cancer effect to cisplatin in non-small cell lung cancer (NSCLC) cell lines. Moreover, we observed that the number of sulfur atoms in polysulfide well reflected the efficacy of these molecules not only in cell protection but also cancer inhibition which may serve as a guide for further development of polysulfide donors for pharmaceutical usage. Taken together, our study suggests that polysulfide may be a novel and promising therapeutic agent to prevent cisplatin-induced nephrotoxicity.