Dexamethasone reduces cisplatin-induced ototoxicity by inducing cisplatin resistance through metallothionein-2

Abstract

Purpose Ototoxicity is a common side effect caused by the anticancer drug cisplatin (CDDP), which reduces patient quality of life. One CDDP-resistance mechanism that occurs in recurrent cancers is heavy metal detoxification by metallothionein-2 (mt2). Here, we show that in zebrafish larvae, dexamethasone (DEX) reduces CDDP-induced ototoxicity. Methods Transgenic zebrafish (cldn: gfp; atoh1: rfp) that express green and red fluorescent protein neuromasts and hair cells were used. The zebrafish were pretreated with mt2 inducers at 52 h post-fertilization (hpf) for 8 h, followed by CDDP treatment for 12 h. The lateral line hair cells of CDDP-treated zebrafish at 72 hpf were observed by fluorescence microscopy. Results The Reporting Odds ratio (ROR) decreased after the American Society of Clinical Oncology (ASCO) first guideline recommended DEX as an antiemetic treatment for cancer chemotherapy in 1999. Pretreatment with DEX protected 72 hpf zebrafish hair cells from CDDP-induced toxicity. The expression of mt2 mRNA was significantly increased by the combination of 10 µM DEX with CDDP. mt2 gene editing reversed the protective effect of DEX against CDDP-induced damage in hair cells. Conclusion DEX prevents hair cells from CDDP-induced ototoxicity mediated by increased mt2 expression, which is a resistance mechanism for platinum-based anticancer drugs.