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.
摘要：
耳毒性是顺铂化疗的主要剂量限制性副作用之一，极大地损害了肿瘤患者的生活质量。由于目前尚无针对顺铂治疗中听力损失的标准治疗方法，本研究的目的是探讨尼莫地平在顺铂相关听力细胞损伤中的作用及其在细胞存活中的作用。为了确定细胞毒性作用，使用未分化和分化的UB/OC-1和UB/OC-2细胞测量细胞死亡率，尼莫地平预处理和顺铂应激诱导后。此外，进行免疫印迹分析和细胞内钙测量以研究抗凋亡信号,这与尼莫地平预处理后细胞毒性作用降低有关。尼莫地平可显着减弱顺铂的细胞毒性作用，高达61％。此外,尼莫地平预处理抵消了顺铂对仅LIM结构域4（LMO4）的减少，这与Ak菌株转化/蛋白激酶B（Akt）的激活增加有关，cAMP反应元件结合蛋白（CREB），和信号转导和转录激活因子3(Stat3)。因此，尼莫地平对顺铂的耳毒性具有潜在的耐受性，这可能会显著改善患者的生活质量。
