Panax notoginseng Saponins protect auditory cells against cisplatin-induced ototoxicity by inducing the AKT/Nrf2 signaling-mediated redox pathway

Cisplatin-induced cytotoxicity, such as nephrotoxicity, neurotoxicity and ototoxicity, restricts the clinical application of this compound. Panax notoginseng Saponins (PNS) exhibit potent free radical scavenging and antioxidant activity. PNS have been demonstrated to reduce cisplatin-induced nephrotoxicity and neurotoxicity. The present study investigated the ability of PNS to protect the auditory HEI-OC1 cell line against ototoxicity induced by cisplatin. PNS induced activation of the AKT/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Following pretreatment with PNS, HEI-OC1 cells were treated with cisplatin and cultured for 24 h. The viability of HEI-OC1 cells was examined using a Cell Counting Kit-8 assay. Double staining analysis was used to measure cell apoptosis. The ability of PNS to reduce reactive oxygen species (ROS) levels was assessed by flow cytometry. The levels of phosphorylated (p)-AKT, heme oxygenase 1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), glutamate-cysteine ligase catalytic (GCLC) and Nrf2 were measured by western blotting. HEI-OC1 cells that were pretreated with PNS exhibited significantly increased cell viability compared with that noted in cells treated only with cisplatin. In addition, PNS suppressed the induction of apoptosis and ROS production following cisplatin treatment. The upregulation of NQO1, HO-1 and GCLC expression in PNS-pretreated cells was associated with p-AKT levels and the activation of Nrf2. These findings suggested that PNS protected auditory cells against ototoxicity induced by cisplatin by activating AKT/Nrf2 signaling. PNS may serve as a potential candidate in regulating cisplatin-induced cytotoxicity.