Article
Nimodipine pre-treatment protects auditory hair cells from cisplatin-induced cell death by upregulation of LMO4
Protektive Wirkung von Nimodipin bei Cisplatin-assoziierter Ototoxizität
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Published: | May 25, 2022 |
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Objective: Ototoxicity is known as one of the main side effects of cisplatin treatment and limits the quality of life of tumor patients, which is already impaired by their disease and important for recovery. Since there is no established therapy at the current time, the aim of this study was focused on the relationship between the neuroprotective effect of nimodipine in relation to the expression of LMO4 and its central role in cell survival in cisplatin-associated cell damage to auditory cells.
Methods: The undifferentiated and differentiated immortalized cell lines UB/OC-1 and UB/OC-2 were used. To investigate the cytotoxic effect, the cell death rate was measured, after nimodipine pre-treatment and stress induction by cisplatin based on the activity of lactate dehydrogenase (LDH) in the supernatant of the cells. Furthermore, Western Blot were performed to investigate anti-apoptotic signalling that may be associated with reduced cytotoxic effect after nimodipine pre-treatment. In addition, the protein level of LMO4 and known interacting proteins, Akt, CREB and Stat3 were analysed. The impact of intracellular calcium concentration under nimodipine pre-treatment and stress induction by cisplatin was detected by the fluorescent dye Cal-520.
Results: The cytotoxic effect by cisplatin on hair cells is attenuated by nimodipine in a dose-dependent manner and led to a significant reduction of cell death up to 65 % (p<0.05) in undifferentiated cells and even after differentiation, a reduction of 40 % (not significant) was still visible. The study confirmed that LMO4 is downregulated by cisplatin. Whereas nimodipine pre-treatment counteracted this reduction, which is associated with increased activation of Akt, CREB, and Stat3 upon cisplatin application. A calcium dependence of the protective effect of nimodipine could not be demonstrated, rather, an increase of intracellular calcium under stress regardless of nimodipine pre-treatment was detected.
Conclusion: By reducing the side effects of cisplatin through nimodipine pre-treatment, a significant improvement in patients' quality of life and better utilization of the chemotherapeutic effect could be achieved. Not only in adults, but especially in children who suffer from a high rate of hearing loss.