Dexamethasone reduces cisplatin-induced hair cell damage by inducing cisplatin resistance through metallothionein-2.

Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7806519 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0843 (Electronic) Linking ISSN: 03445704 NLM ISO Abbreviation: Cancer Chemother Pharmacol Subsets: MEDLINE

Publication: Berlin : Springer Verlag
Original Publication: Berlin, New York, Springer International.

Antineoplastic Agents*/pharmacology ; Cisplatin*/adverse effects ; Dexamethasone*/pharmacology ; Drug Resistance, Neoplasm*/drug effects ; Hair Cells, Auditory*/drug effects ; Hair Cells, Auditory*/metabolism ; Hair Cells, Auditory*/pathology ; Metallothionein*/genetics ; Metallothionein*/metabolism; Animals ; Humans ; Animals, Genetically Modified ; Zebrafish ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism

Purpose: Hair cell damage 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 hair cell damage by enhancing mt2 expression.
Methods: Transgenic zebrafish (cldn: gfp; atoh1: rfp) that express green and red fluorescent proteins in neuromasts and hair cells, respectively, were used. The zebrafish were pretreated with DEX 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: Reporting odds ratio (ROR) analysis using an adverse event database indicated an association between a decrease in CDDP-induced ototoxicity and DEX as an antiemetic treatment for cancer chemotherapy. Pretreatment with DEX protected 72 hpf zebrafish hair cells from CDDP-induced damage. The expression of mt2 mRNA was significantly increased by the combination of 10 µM DEX with CDDP. Gene editing of mt2 reversed the protective effect of DEX against CDDP-induced damage in hair cells.
Conclusion: DEX protects hair cells from CDDP-induced damage through increased mt2 expression, which is a resistance mechanism for platinum-based anticancer drugs.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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Keywords: Cisplatin; Dexamethasone; Hair cell damage; Metallothionein-2; Zebrafish hair cells

0 (Antineoplastic Agents)
Q20Q21Q62J (Cisplatin)
7S5I7G3JQL (Dexamethasone)
9038-94-2 (Metallothionein)
0 (Zebrafish Proteins)

Date Created: 20240814 Date Completed: 20240928 Latest Revision: 20241004

20241004

10.1007/s00280-024-04706-z

39141082