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.

Impact of the Voltage-Gated Calcium Channel Antagonist Nimodipine on the Development of Oligodendrocyte Precursor Cells

“…Future studies will have to demonstrate if nimodipine has the potential to become such a drug. Although beneficial effects of nimodipine have been shown on remyelination both in vivo [ 20 , 21 ] and in vitro, in addition to the effects on astrocytes, microglia, and neurons [ 20 , 22 , 23 , 25 , 84 ], these effects could not be explained by a VGCC-dependent mode of action in all cases [ 22 , 25 , 84 ]. Therefore, further investigation is necessary to identify potential interaction partners of nimodipine at a cellular level, which would clarify its role and potential in (re-) myelination.…”

Cisplatin ototoxicity mechanism and antagonistic intervention strategy: a scope review

“…5,7-Dihydroxy-4-methylcoumarin (D4M) markedly regulated p-c-Jun N-terminal kinase (p-JNK) and elevated the expression ratio of p-FoxO1/FoxO1, thus attenuating SGNs injury, mitochondrial dysfunction, ROS accumulation and cisplatin-induced caspase-dependent apoptosis ( Li et al, 2023 ). As a calcium channel antagonist with lipophilic properties, nimodipine pre-treatment could significantly reduce cisplatin-induced apoptosis via regulating LIM domain only 4 (LMO4) levels and activating associated Akt, cAMP-response element binding protein (CREB), and Signal transducer and activator of transcription 3 (Stat3) protein levels ( Fritzsche et al, 2022 ; Table 3 ).…”

New Advancements in Cisplatin-Based Treatments

“…Many different drugs and natural products reduce cisplatin toxicity [ 3 , 5 ]. A recent study showed that nimodipine pre-treatment of auditory cells decreases cisplatin-induced cell death in vitro [ 6 ]. Cisplatin-based chemotherapy increases the formation of reactive oxygen and nitrogen species, triggering oxidative modification of cochlear proteins and leading to the downregulation of the otoprotective transcription regulator LIM Domain Only 4 (LMO4) [ 7 ].…”

“…Cisplatin-based chemotherapy increases the formation of reactive oxygen and nitrogen species, triggering oxidative modification of cochlear proteins and leading to the downregulation of the otoprotective transcription regulator LIM Domain Only 4 (LMO4) [ 7 ]. Nimodipine pre-treatment upregulates LMO4 and ultimately activates antiapoptotic pathways, reducing cisplatin ototoxicity [ 6 ]. In addition, emerging research has demonstrated the importance of treatment formulation beyond the treatment itself to prevent/reduce cisplatin toxicity.…”