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National Institute of Environmental Health Sciences

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Publication Detail

Title: Targeting nitrative stress for attenuating cisplatin-induced downregulation of cochlear LIM domain only 4 and ototoxicity.

Authors: Jamesdaniel, Samson; Rathinam, Rajamani; Neumann, William L

Published In Redox Biol, (2016 Dec)

Abstract: Cisplatin-induced ototoxicity remains a primary dose-limiting adverse effect of this highly effective anticancer drug. The clinical utility of cisplatin could be enhanced if the signaling pathways that regulate the toxic side-effects are delineated. In previous studies, we reported cisplatin-induced nitration of cochlear proteins and provided the first evidence for nitration and downregulation of cochlear LIM domain only 4 (LMO4) in cisplatin ototoxicity. Here, we extend these findings to define the critical role of nitrative stress in cisplatin-induced downregulation of LMO4 and its consequent ototoxic effects in UBOC1 cell cultures derived from sensory epithelial cells of the inner ear and in CBA/J mice. Cisplatin treatment increased the levels of nitrotyrosine and active caspase 3 in UBOC1 cells, which was detected by immunocytochemical and flow cytometry analysis, respectively. The cisplatin-induced nitrative stress and apoptosis were attenuated by co-treatment with SRI110, a peroxynitrite decomposition catalyst (PNDC), which also attenuated the cisplatin-induced downregulation of LMO4 in a dose-dependent manner. Furthermore, transient overexpression of LMO4 in UBOC1 cells prevented cisplatin-induced cytotoxicity while repression of LMO4 exacerbated cisplatin-induced cell death, indicating a direct link between LMO4 protein levels and cisplatin ototoxicity. Finally, auditory brainstem responses (ABR) recorded from CBA/J mice indicated that co-treatment with SRI110 mitigated cisplatin-induced hearing loss. Together, these results suggest that cisplatin-induced nitrative stress leads to a decrease in the levels of LMO4, downregulation of LMO4 is a critical determinant in cisplatin-induced ototoxicity, and targeting peroxynitrite could be a promising strategy for mitigating cisplatin-induced hearing loss.

PubMed ID: 27821327 Exiting the NIEHS site

MeSH Terms: Adaptor Proteins, Signal Transducing/metabolism*; Animals; Antineoplastic Agents/toxicity*; Apoptosis/drug effects; Cells, Cultured; Cisplatin/toxicity*; Cochlea/cytology; Cochlea/drug effects; Cochlea/metabolism*; Disease Models, Animal; Down-Regulation/drug effects*; Evoked Potentials, Auditory, Brain Stem; Hearing Loss/chemically induced; Hearing Loss/metabolism*; LIM Domain Proteins/metabolism*; Manganese Compounds/administration & dosage*; Manganese Compounds/chemistry; Manganese Compounds/pharmacology; Membrane Proteins/metabolism; Mice; Mice, Inbred CBA; Peroxynitrous Acid/analogs & derivatives; Serpins/metabolism; Signal Transduction/drug effects; Tyrosine/analogs & derivatives; Tyrosine/metabolism

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