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Updated: Mar 12, 2026
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Targeting nitrative stress for attenuating cisplatin-induced downregulation of cochlear LIM domain only 4 and
Samson Jamesdaniel1, Rajamani Rathinam2, William L Neumann3
1Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA; Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, MI 48202, USA.
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.
Insights
Cisplatin causes hearing loss by reducing LMO4 protein levels via nitrative stress. Protecting against this stress with SRI110 may prevent cisplatin ototoxicity.
Area of Science:
- Ototoxicity research
- Cancer drug side effects
- Inner ear cell biology
Background:
- Cisplatin is a vital chemotherapy drug, but its use is limited by ototoxicity.
- Previous work identified cochlear protein nitration and LIM domain only 4 (LMO4) downregulation in cisplatin ototoxicity.
Purpose of the Study:
- To investigate the role of nitrative stress in cisplatin-induced LMO4 downregulation and ototoxicity.
- To evaluate the therapeutic potential of targeting nitrative stress to prevent hearing loss.
Main Methods:
- Utilized UBOC1 inner ear cell cultures and CBA/J mice models.
- Assessed nitrative stress markers (nitrotyrosine) and apoptosis (active caspase 3).
- Examined LMO4 protein levels and cell viability following cisplatin and SRI110 (peroxynitrite decomposition catalyst) treatment.
- Measured auditory brainstem responses (ABR) in mice.
Main Results:
- Cisplatin increased nitrative stress and apoptosis in UBOC1 cells.
- SRI110 attenuated cisplatin-induced nitrative stress, apoptosis, and LMO4 downregulation.
- LMO4 overexpression protected against cisplatin cytotoxicity; LMO4 repression worsened it.
- SRI110 treatment mitigated cisplatin-induced hearing loss in mice.
Conclusions:
- Cisplatin-induced nitrative stress decreases LMO4 levels, a key factor in ototoxicity.
- Targeting peroxynitrite with catalysts like SRI110 shows promise for preventing cisplatin-induced hearing loss.
