MnTBAP, a peroxynitrite scavenger, attenuates cisplatin-induced apoptosis and cytotoxicity in organ of Corti cells

Cisplatin, a widely used anti-cancer drug, induces apoptosis in cochlear hair cells. In previous studies, cisplatin-induced nitration and degradation of proteins such as LMO4 disrupted their anti-apoptotic signaling. Cotreatment with SRI110, a peroxynitrite decomposition catalyst, attenuated cisplatin-induced ototoxicity in rodents. However, it is not known if other compounds that target nitrative stress would also confer similar otoprotection. Manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP), a cell-permeable superoxide dismutase mimetic, is a peroxynitrite decomposition catalyst that selectively scavenges peroxynitrite. This study demonstrates that cotreatment of UB/OC1 cells MnTBAP prevented cisplatin-induced cytotoxicity and nitrative stress. Furthermore, the mRNA levels of pro-apoptotic genes such as <i>Caspase-3, Caspase-9, Fas, Fadd,</i> and <i>Bcl2</i> that were upregulated by cisplatin treatment were attenuated by MnTBAP cotreatment. The cisplatin-induced downregulation of <i>Prdx2</i>, an antioxidant gene, was significantly attenuated by MnTBAP cotreatment. Immunoblot analysis demonstrated that cisplatin-induced reduction in the expression of LMO4 protein was attenuated when the cells were cotreated with MnTBAP. Together, these results indicate that MnTBAP cotreatment attenuates cisplatin-induced apoptosis and mitigates associated cytotoxicity in UB/OC1 cell lines suggesting that peroxynitrite decomposition catalysts could emerge as promising interventional compounds for preventing cisplatin-induced ototoxicity.