Epicatechin protects the auditory organ by attenuating cisplatin-induced ototoxicity through inhibition of ERK.
Cisplatin, a widely used chemotherapeutic drug, causes ototoxicity in a large percentage of patients. The purpose of this study was to determine the efficacy of epicatechin (EC) as an otoprotective agent to prevent cisplatin toxicity and to investigate the molecular mechanism of EC. The effects of EC on cisplatin-induced ototoxicity were investigated in a cochlear organ of Corti-derived cell line, HEI-OC1 and in a rat model. In addition, signaling mechanisms were investigated, specifically those involving MAP kinase. Cisplatin induced apoptosis and demonstrated, conjugation of annexin V/PI in FACS, and an increase of subG1 in HEI-OC1. EC protected HEI-OC1 against cisplatin and showed inhibition of cisplatin-induced apoptosis of the HEI-OC1 by transmission electron microscopy. Intratympanic administration of EC protected against cisplatin-induced ototoxicity in the rat model, as determined by auditory brainstem responses. EC inhibited activation of JNK, ERK, cytochrome-c and caspase-3 by cisplatin. An ERK Inhibitor, cisplatin-induced ototoxicity in a dose dependent manner but a JNK inhibitor did not. The results of this study suggest that EC may provide a mechanism by which ototoxicity caused by the administration of cisplatin can be reduced through the inhibition of ERK. EC may have clinical use as a chemopreventive agent that prevents cisplatin ototoxicity.
Lee
J S
JS
Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea.
Kang
S U
SU
Hwang
H S
HS
Pyun
J H
JH
Choung
Y H
YH
Kim
C H
CH
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002392:Catechin / Q000494:pharmacology*; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D034381:Hearing Loss / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D002392:Catechin; D048049:Extracellular Signal-Regulated MAP Kinases; D002945:Cisplatin