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

Abstract

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.