PUBLICATION
Dexamethasone reduces cisplatin-induced hair cell damage by inducing cisplatin resistance through metallothionein-2
- Authors
- Ujiie, H., Nishiya, N., Yamamoto, A., Takada, T., Onodera, M., Sasaki, A., Oikawa, T.
- ID
- ZDB-PUB-240815-2
- Date
- 2024
- Source
- Cancer Chemotherapy and Pharmacology 94(4): 561-569 (Journal)
- Registered Authors
- Keywords
- Cisplatin, Dexamethasone, Hair cell damage, Metallothionein-2, Zebrafish hair cells
- MeSH Terms
-
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Antineoplastic Agents*/pharmacology
- Zebrafish
- Animals
- Humans
- Hair Cells, Auditory*/drug effects
- Hair Cells, Auditory*/metabolism
- Hair Cells, Auditory*/pathology
- Metallothionein*/genetics
- Metallothionein*/metabolism
- Animals, Genetically Modified
- Dexamethasone*/pharmacology
- Drug Resistance, Neoplasm*/drug effects
- Cisplatin*/adverse effects
- PubMed
- 39141082 Full text @ Cancer Chemother. Pharmacol.
Citation
Ujiie, H., Nishiya, N., Yamamoto, A., Takada, T., Onodera, M., Sasaki, A., Oikawa, T. (2024) Dexamethasone reduces cisplatin-induced hair cell damage by inducing cisplatin resistance through metallothionein-2. Cancer Chemotherapy and Pharmacology. 94(4):561-569.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping