title: Protective effect of T-type calcium channel blocker flunarizine on cisplatin-induced death of auditory cells.
abstract: Changes in intracellular Ca2+ level are involved in a number of intracellular events, including triggering of apoptosis. The role of intracellular calcium mobilization in cisplatin-induced hair cell death, however, is still unknown. In this study, the effect of calcium channel blocker flunarizine (Sibelium), which is used to prescribe for vertigo and tinnitus, on cisplatin-induced hair cell death was investigated in a cochlear organ of Corti-derived cell line, HEI-OC1, and the neonatal (P2) rat organ of Corti explant. Cisplatin induced apoptotic cell death showing nuclear fragmentation, DNA ladder, and TUNEL positive in both HEI-OC1 and primary organ of Corti explant. Flunarizine significantly inhibited the cisplatin-induced apoptosis. Unexpectedly, flunarizine increased the intracellular calcium ([Ca2+]i) levels of HEI-OC1. However, the protective effect of flunarizine against cisplatin was not mediated by modulation of intracellular calcium level. Treatment of cisplatin resulted in ROS generation and lipid peroxidation in HEI-OC1. Flunarizine did not attenuate ROS production but inhibited lipid peroxidation and mitochondrial permeability transition in cisplatin-treated cells. This result suggests that the protective mechanism of flunarizine on cisplatin-induced cytotoxicity is associated with direct inhibition of lipid peroxidation and mitochondrial permeability transition.
authors.affiliation: Vestibulocochlear Research Center and Department of Microbiology, Korea Basic Science Institute, Taejon 305-333, Korea.
authors.forename: Hong-Seob
authors.initials: HS
authors.lastname: So
authors.forename: Channy
authors.initials: C
authors.lastname: Park
authors.forename: Hyung-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jung-Han
authors.initials: JH
authors.lastname: Lee
authors.forename: Sung-Yeol
authors.initials: SY
authors.lastname: Park
authors.forename: Jai-Hyung
authors.initials: JH
authors.lastname: Lee
authors.forename: Zee-Won
authors.initials: ZW
authors.lastname: Lee
authors.forename: Hyung-Min
authors.initials: HM
authors.lastname: Kim
authors.forename: Federico
authors.initials: F
authors.lastname: Kalinec
authors.forename: David J
authors.initials: DJ
authors.lastname: Lim
authors.forename: Raekil
authors.initials: R
authors.lastname: Park
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D020747:Calcium Channels, T-Type / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002945:Cisplatin / Q000009:adverse effects*; D005444:Flunarizine / Q000008:administration & dosage / Q000627:therapeutic use*; D006198:Hair Cells, Auditory / Q000187:drug effects*; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced / Q000517:prevention & control* / Q000628:therapy; D020287:In Situ Nick-End Labeling; D015227:Lipid Peroxidation / Q000187:drug effects; D009924:Organ Culture Techniques; D009925:Organ of Corti / Q000166:cytology / Q000187:drug effects; D020011:Protective Agents / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D020011:Protective Agents; D017382:Reactive Oxygen Species; D002945:Cisplatin; D005444:Flunarizine