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Susceptibility of mouse cochlear hair cells to cisplatin ototoxicity largely depends on sensory mechanoelectrical transduction channels both Ex Vivo and In Vivo.
Maruyama, Ayako; Kawashima, Yoshiyuki; Fukunaga, Yoko; Makabe, Ayane; Nishio, Ayako; Tsutsumi, Takeshi.
Afiliação
  • Maruyama A; Department of Otolaryngology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
  • Kawashima Y; Department of Otolaryngology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Electronic address: kawashima.oto1@mac.com.
  • Fukunaga Y; Department of Otolaryngology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, 54, Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
  • Makabe A; Department of Otolaryngology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
  • Nishio A; Department of Otolaryngology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
  • Tsutsumi T; Department of Otolaryngology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Hear Res ; 447: 109013, 2024 06.
Article em En | MEDLINE | ID: mdl-38718672
ABSTRACT
Cisplatin, a highly effective chemotherapeutic drug for various human cancers, induces irreversible sensorineural hearing loss as a side effect. Currently there are no highly effective clinical strategies for the prevention of cisplatin-induced ototoxicity. Previous studies have indicated that short-term cisplatin ototoxicity primarily affects the outer hair cells of the cochlea. Therefore, preventing the entry of cisplatin into hair cells may be a promising strategy to prevent cisplatin ototoxicity. This study aimed to investigate the entry route of cisplatin into mouse cochlear hair cells. The competitive inhibitor of organic cation transporter 2 (OCT2), cimetidine, and the sensory mechanoelectrical transduction (MET) channel blocker benzamil, demonstrated a protective effect against cisplatin toxicity in hair cells in cochlear explants. Sensory MET-deficient hair cells explanted from Tmc1Δ;Tmc2Δ mice were resistant to cisplatin toxicity. Cimetidine showed an additive protective effect against cisplatin toxicity in sensory MET-deficient hair cells. However, in the apical turn, cimetidine, benzamil, or genetic ablation of sensory MET channels showed limited protective effects, implying the presence of other entry routes for cisplatin to enter the hair cells in the apical turn. Systemic administration of cimetidine failed to protect cochlear hair cells from ototoxicity caused by systemically administered cisplatin. Notably, outer hair cells in MET-deficient mice exhibited no apparent deterioration after systemic administration of cisplatin, whereas the outer hair cells in wild-type mice showed remarkable deterioration. The susceptibility of mouse cochlear hair cells to cisplatin ototoxicity largely depends on the sensory MET channel both ex vivo and in vivo. This result justifies the development of new pharmaceuticals, such as a specific antagonists for sensory MET channels or custom-designed cisplatin analogs which are impermeable to sensory MET channels.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cimetidina / Cisplatino / Mecanotransdução Celular / Transportador 2 de Cátion Orgânico / Ototoxicidade / Antineoplásicos Limite: Animals Idioma: En Revista: Hear Res Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Japão

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cimetidina / Cisplatino / Mecanotransdução Celular / Transportador 2 de Cátion Orgânico / Ototoxicidade / Antineoplásicos Limite: Animals Idioma: En Revista: Hear Res Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Japão