Nimodipine Treatment Protects Auditory Hair Cells from Cisplatin-Induced Cell Death Accompanied by Upregulation of LMO4

Abstract

Ototoxicity is one of the main dose-limiting side effects of cisplatin chemotherapy and impairs the quality of life of tumor patients dramatically. Since there is currently no established standard therapy targeting hearing loss in cisplatin treatment, the aim of this study was to investigate the effect of nimodipine and its role in cell survival in cisplatin-associated hearing cell damage. To determine the cytotoxic effect, the cell death rate was measured using undifferentiated and differentiated UB/OC−1 and UB/OC−2 cells, after nimodipine pre-treatment and stress induction by cisplatin. Furthermore, immunoblot analysis and intracellular calcium measurement were performed to investigate anti-apoptotic signaling, which was associated with a reduced cytotoxic effect after nimodipine pre-treatment. Cisplatin’s cytotoxic effect was significantly attenuated by nimodipine up to 61%. In addition, nimodipine pre-treatment counteracted the reduction in LIM Domain Only 4 (LMO4) by cisplatin, which was associated with increased activation of Ak strain transforming/protein kinase B (Akt), cAMP response element-binding protein (CREB), and signal transducers and activators of transcription 3 (Stat3). Thus, nimodipine presents a potentially well-tolerated substance against the ototoxicity of cisplatin, which could result in a significant improvement in patients’ quality of life.