Is S-nitrosylation of Cochlear Proteins a Critical Factor in Cisplatin-Induced Ototoxicity?

Abstract

S-nitrosylation is a redox-sensitive protein modification, which is a highly specific, but reversible mechanism that regulates several signal transduction cascades. Oxidative stress plays a causal role in the ototoxic effects of an antineoplastic drug, cisplatin. Despite emerging evidence implicating nitroxidative stress as a critical factor in cisplatin toxicity, the significance of the cochlear protein S-nitrosylation in cisplatin ototoxicity is yet to be understood. In the present study, a 16-mg/kg dose of cisplatin, induced a significant shift in the amplitudes of distortion product otoacoustic emissions, a measure of outer hair cell activity, in Wistar rats, 3 days post-treatment. These ototoxic effects were accompanied by significant increases in the S-nitrosylation of at least three cochlear proteins. Biological significance of these S-nitrosylated proteins was indicated by their immunolocalization in organ of Corti, stria vascularis, and spiral ganglions, which are known cochlear targets of cisplatin toxicity. In addition, co-treatment with Trolox, an inhibitor of peroxynitrite, attenuated cisplatin-induced S-nitrosylation of cochlear proteins and prevented the associated hearing loss. The cisplatin-induced S-nitrosylation of inner ear proteins, their sensitive cochlear localization, and their potential association with cisplatin-induced hearing loss suggests that S-nitrosylation of cochlear proteins might play a crucial role in mediating cisplatin ototoxicity. Antioxid. Redox Signal. 17, 929-933.

Prevention and Restoration of Hearing Loss Associated with the Use of Cisplatin

“…Molecular mechanisms of cisplatin-induced hearing loss involve the creation of reactive oxygen species and depletion of antioxidant glutathione and its regenerating enzymes as well as increased rate of lipid peroxidation, oxidative modifications of proteins, nucleic acids damage by caspase system activation [ 3 ], and S-nitrosylation of cochlear proteins and resulting apoptosis of inner ear cells [ 7 ].…”

Curcuma Longa (Curcumin) Decreases In Vivo Cisplatin-Induced Ototoxicity Through Heme Oxygenase-1 Induction

“…Finally, curcumin did not influence the anticancer efficacy of cisplatin as detected by the time-dependent increase in weight loss observed 3 and 5 days after cisplatin treatment in both groups (57). Moreover, several evidences (15,16,58,59) have underlined the anticancer properties of curcumin as a means of sensitizing cancer cells to cisplatin.…”

Cisplatin-induced apoptosis in auditory, renal, and neuronal cells is associated with nitration and downregulation of LMO4

“… 34 Cisplatin-induced nitration and nitrosylation of proteins have been reported in the cochlea, and nitrated proteins were localized to cells known to be targeted by cisplatin, particularly outer hair cells. 5 , 35 Cisplatin-induced increase in nitrotyrosine was detected in damaged renal tubular cells in mice, 72 h post treatment. 12 Nitrite levels were reported to be significantly elevated in the brain of cisplatin-treated mice.…”