Cisplatin is a platinum(II) chemotherapy drug that can cause the side-effect of ototoxicity and hearing loss. The monofunctional platinum(II) complexes, phenanthriplatin and pyriplatin, have recently been investigated as anti-cancer agents but their side-effects are largely unknown. Here, we used the auditory hybridoma cell line, HEI-OC1, to investigate the ototoxicity of cisplatin, phenanthriplatin and pyriplatin. The effect of these compounds against cellular viability, on reactive oxygen species (ROS) production, mitochondrial membrane polarization, caspase-3/7 activity, DNA integrity and caspase-12 expression were measured using spectrophotometric, flow cytometric and blot analyses. We found that the monofunctional complexes and cisplatin decreased cellular viability. All three compounds increased ROS yield at 24 hours, but at 48 hours, ROS levels returned to normal. Also, the compounds did not depolarize the mitochondrial membrane. All three compounds reduced caspase-3/7 activity at 24 hours; cisplatin increased caspase-3/7 activity and caused apoptosis at 48 hours. Caspase-12 expression was associated with all three compounds. In summary, the monofunctional complexes may cause ototoxicity like cisplatin. Phenanthriplatin and pyriplatin may cause ototoxicity initially by inducing ROS production, but they may also signal through distinct apoptotic pathways that do not integrate caspases-3/7, or may act at different time-points in the same pathways.

中文翻译：

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单功能的铂（II）化合物，菲铂和吡铂调节HEI-OC1听觉杂交瘤细胞的凋亡信号通路。

顺铂是铂（II）化疗药物，可引起耳毒性和听力损失的副作用。最近已经研究了单功能的铂（II）配合物菲咯铂和吡铂作为抗癌药，但它们的副作用尚不清楚。在这里，我们使用听觉杂交瘤细胞系HEI-OC1来研究顺铂，菲铂和吡铂的耳毒性。使用分光光度法，流式细胞仪和印迹分析法测量了这些化合物对细胞活力，活性氧（ROS）产生，线粒体膜极化，caspase-3 / 7活性，DNA完整性和caspase-12表达的影响。我们发现单功能复合物和顺铂降低细胞活力。这三种化合物均可在24小时提高ROS产量，但在48小时时，ROS水平恢复正常。而且，该化合物不会使线粒体膜去极化。所有这三种化合物均在24小时降低了caspase-3 / 7的活性。顺铂增加caspase-3 / 7活性并在48小时引起细胞凋亡。Caspase-12表达与所有这三种化合物有关。总之，单功能复合物可能会引起顺铂等耳毒性。苯并蒽铂和吡铂最初可能通过诱导ROS产生而引起耳毒性，但它们也可能通过不整合caspases-3 / 7的不同凋亡途径发出信号，或者可能在同一途径的不同时间点起作用。Caspase-12表达与所有这三种化合物有关。总之，单功能复合物可能会引起顺铂等耳毒性。苯并蒽铂和吡铂最初可能通过诱导ROS产生而引起耳毒性，但它们也可能通过不整合caspases-3 / 7的不同凋亡途径发出信号，或者可能在同一途径的不同时间点起作用。Caspase-12表达与所有这三种化合物有关。总之，单功能复合物可能会引起顺铂等耳毒性。苯并蒽铂和吡铂最初可能通过诱导ROS产生而引起耳毒性，但它们也可能通过不整合caspases-3 / 7的不同凋亡途径发出信号，或者可能在同一途径的不同时间点起作用。