PUBLICATION
Ferrostatin-1 protects auditory hair cells from cisplatin-induced ototoxicity in vitro and in vivo
- Authors
- Hu, B., Liu, Y., Chen, X., Zhao, J., Han, J., Dong, H., Zheng, Q., Nie, G.
- ID
- ZDB-PUB-201029-2
- Date
- 2020
- Source
- Biochemical and Biophysical Research Communications 533(4): 1442-1448 (Journal)
- Registered Authors
- Keywords
- Cisplatin ototoxicity, Ferroptosis, Ferrostatin-1, Hair cell
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Cells, Cultured
- Cisplatin/adverse effects*
- Cochlea/cytology
- Cochlea/drug effects
- Cyclohexylamines/administration & dosage
- Cyclohexylamines/pharmacology*
- Dose-Response Relationship, Drug
- Female
- Hair Cells, Auditory/drug effects*
- Hair Cells, Auditory/metabolism
- Hair Cells, Auditory/pathology
- Humans
- Male
- Mice, Inbred C57BL
- Mitochondria/drug effects
- Mitochondria/metabolism
- Mitochondria/pathology
- Organ Culture Techniques
- Ototoxicity/drug therapy*
- Ototoxicity/etiology
- Phenylenediamines/administration & dosage
- Phenylenediamines/pharmacology*
- Protective Agents/administration & dosage
- Protective Agents/pharmacology
- Reactive Oxygen Species/metabolism
- Zebrafish/genetics
- PubMed
- 33109343 Full text @ Biochem. Biophys. Res. Commun.
Citation
Hu, B., Liu, Y., Chen, X., Zhao, J., Han, J., Dong, H., Zheng, Q., Nie, G. (2020) Ferrostatin-1 protects auditory hair cells from cisplatin-induced ototoxicity in vitro and in vivo. Biochemical and Biophysical Research Communications. 533(4):1442-1448.
Abstract
Cisplatin is used in a wide variety of malignancies, but cisplatin-induced ototoxicity remains a major issue in clinical practice. Experimental evidence indicates that ferroptosis plays a key role in mediating the unwanted cytotoxicity effect caused by cisplatin. However, the role of ferroptosis in cisplatin-induced ototoxicity requires elucidation. Ferrostatin-1 (Fer-1) was identified as a potent inhibitor of ferroptosis and radical-trapping antioxidant with its ability to reduce the accumulation of lipid peroxides and chain-carrying peroxyl radicals. In the current study, we investigated the effects of Fer-1 in cisplatin-induced ototoxicity in in vitro, ex vivo, and in vivo models. We found, for the first time that Fer-1 efficiently alleviated cisplatin-induced cytotoxicity in HEI-OC1 cells via a concentration-dependent manner. Furthermore, Fer-1 mitigated cisplatin cytotoxicity in transgenic zebrafish sensory hair cells. In HEI-OC1 cells, Fer-1 pretreatment not only drastically reduced the generation of intracellular reactive oxygen species but also remarkably decreased lipid peroxidation levels induced by cisplatin. This was not only ascribed to the inhibition of 4-hydroxynonenal, the final product of lipid peroxides, but also to the promotion of glutathione peroxidase 4, the protein marker of ferroptosis. MitoTracker staining and transmission electron microscopy of mitochondrial morphology suggested that in HEI-OC1 cells, Fer-1 can effectively abrogate mitochondrial damage resulting from the interaction with cisplatin. In addition, Fer-1 pretreatment of cochlear explants substantially protected hair cells from cisplatin-induced damage. Therefore, our results demonstrated that ferroptosis might be involved in cisplatin ototoxicity. Fer-1 administration mitigated cisplatin-induced hair cell damage, further investigations are required to elucidate the molecular mechanisms of its otoprotective effect.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping