The present study is conducted to determine the mechanism of renal protective effect of polysulfide to prevent nephrotoxicity caused by a chemotherapeutic drug cisplatin

Cisplatin is a widely used chemotherapeutic drug for solid tumors arising from multiple organs such as head and neck, testicular, cervical, ovaries, lung and bladder; however, clinical studies have revealed that cisplatin usage is accompanied with severe adverse effects including nephrotoxicity, ototoxicity, and neurotoxicity.

Despite being a well-known and influential anti-proliferative drug, cisplatin usage is accompanied with moderate-to-severe adverse effects. Cisplatin-induced nephrotoxicity stands as the primary factor limiting its clinical application due to its prevalence and severity. This urges us to search a possible agent that can prevent cisplatin nephrotoxicity without affecting its anti-cancer activity.

Polysulfide is a category of chemical compounds comprising chains of sulfur atoms. The protective effect of polysulfide was first examined within renal proximal tubular (RPT) cells.

Collected data showed that at a concentration of 80?µM sodium tetrasulfide (Na2S4) almost completely abolished cisplatin-caused LDH release from RPT cells which was slightly reduced by sodium trisulfide (Na2S3) and hardly influenced by sodium disulfide (Na2S2).

Therefore, Na2S4 was used as a polysulfide donor in the following studies. According to Na2Salleviated cisplatin-induced lactate dehydrogenase (LDH) release from RPT cell in a concentration-dependent manner. Na2S4, at 80?µM, also mainly reduced the cisplatin-caused increase of PI-positive cell numbers and cleavage of caspase 3. These results indicate the protective effect of polysulfide in cisplatin-induced RPT cell death.

The 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 can add on more anti-cancer effect to cisplatin in non-small cell lung cancer (NSCLC) cell lines.

Moreover, researchers 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, the study suggests that polysulfide may be a novel and promising therapeutic agent to prevent cisplatin-induced nephrotoxicity.