Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Korea; Center for Cell Death Regulating Biodrug, School of Medicine, Ajou University, Suwon, Korea.
J Appl Toxicol. 2014 Feb;34(2):191-204. doi: 10.1002/jat.2852. Epub 2013 Jan 8.
Cisplatin [cis-diammine-dichloroplatinum (II)] is a widely used chemotherapeutic agent, and one of its most severe side effects is ototoxicity. In the course of developing a new protective agent against cisplatin-induced ototoxicity, we have been interested in a novel synthetic compound, 3-Amino-3-(4-fluoro-phenyl)-1H-quinoline-2,4-dione (KR-22335). We evaluated the effectiveness of KR-22335 as an otoprotective agent against cisplatin-induced toxicity. The otoprotective effect of KR-22335 against cisplatin was tested in vitro in cochlear organs of Corti-derived cell lines, HEI-OC1, and in vivo in a zebrafish (Danio rerio) model. Cisplatin-induced apoptosis, cell cycle arrest and an increase in intracellular reactive oxygen species (ROS) generation were demonstrated in HEI-OC1 cells. KR-22335 inhibited cisplatin-induced apoptosis and mitochondrial injury in HEI-OC1 cells. KR-22335 inhibited cisplatin-induced activation of JNK, p-38, caspase-3 and PARP in HEI-OC1 cells. Scanning and transmission electron micrographs showed that KR-22335 prevented cisplatin-induced destruction of kinocilium and stereocilia in zebrafish neuromasts. Tissue TUNEL of neuromasts in zebrafish demonstrated that KR-22335 blocked cisplatin-induced TUNEL positive hair cells in neuromasts. The results of this study suggest that KR-22335 may prevent ototoxicity caused by the administration of cisplatin through the inhibition of mitochondrial dysfunction and suppression of ROS generation. KR-22335 may be considered as a potential candidate for protective agents against cisplatin-induced ototoxicity.
顺铂（cis-diammine-dichloroplatinum (II)）是一种广泛使用的化疗药物，其最严重的副作用之一是耳毒性。在开发一种新的顺铂诱导耳毒性保护剂的过程中，我们对一种新型合成化合物 3-氨基-3-(4-氟-苯基)-1H-喹啉-2,4-二酮（KR-22335）产生了兴趣。我们评估了 KR-22335 作为顺铂诱导毒性的耳保护剂的有效性。KR-22335 对顺铂的耳保护作用在体外通过耳蜗器官培养的 Corti 衍生细胞系 HEI-OC1 进行了测试，在体内通过斑马鱼（Danio rerio）模型进行了测试。在 HEI-OC1 细胞中，证明了顺铂诱导的细胞凋亡、细胞周期停滞和细胞内活性氧（ROS）生成增加。KR-22335 抑制 HEI-OC1 细胞中顺铂诱导的细胞凋亡和线粒体损伤。KR-22335 抑制 HEI-OC1 细胞中顺铂诱导的 JNK、p-38、caspase-3 和 PARP 的激活。扫描和透射电镜显示，KR-22335 可防止顺铂诱导的斑马鱼毛细胞感受器中的 kinocilium 和 stereocilia 破坏。斑马鱼毛细胞感受器的组织 TUNEL 显示，KR-22335 阻断了顺铂诱导的 TUNEL 阳性毛细胞在毛细胞感受器中的表达。这项研究的结果表明，KR-22335 可能通过抑制线粒体功能障碍和抑制 ROS 生成来预防顺铂引起的耳毒性。KR-22335 可被视为预防顺铂诱导耳毒性的潜在候选药物。
