Novel synthetic protective compound,KR‐22335, against cisplatin‐induced auditory cell death

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. Copyright © 2013 John Wiley & Sons, Ltd.