PUBLICATION
The possible repositioning of an oral anti-arthritic drug, auranofin, for Nrf2-activating therapy: the demonstration of Nrf2-dependent anti-oxidative action using a zebrafish model
- Authors
- Fuse, Y., Endo, Y., Araoi, S., Daitoku, H., Suzuki, H., Kato, M., Kobayashi, M.
- ID
- ZDB-PUB-171227-1
- Date
- 2017
- Source
- Free radical biology & medicine 115: 405-411 (Journal)
- Registered Authors
- Endo, Yuka, Fuse, Yuji, Kobayashi, Makoto
- Keywords
- Nrf2 pathway, arsenite toxicity, auranofin-induced protection, heavy metal, oxidative stress, zebrafish genetics
- MeSH Terms
-
- Animals
- Mutation/genetics
- Administration, Oral
- Antioxidants/pharmacology
- Antioxidants/therapeutic use*
- Hydrogen Peroxide/toxicity
- Antirheumatic Agents/pharmacology
- Antirheumatic Agents/therapeutic use*
- Larva
- Auranofin/pharmacology
- Auranofin/therapeutic use*
- Metals, Heavy/toxicity
- Oxidative Stress/drug effects
- Drug Repositioning
- Disease Models, Animal
- Arthritis/drug therapy*
- NF-E2-Related Factor 2/antagonists & inhibitors*
- NF-E2-Related Factor 2/genetics
- Zebrafish Proteins/antagonists & inhibitors*
- Zebrafish Proteins/genetics
- Humans
- Signal Transduction
- Oxidation-Reduction
- Zebrafish
- Arsenites/toxicity
- Organisms, Genetically Modified
- PubMed
- 29277393 Full text @ Free Radic. Biol. Med.
Citation
Fuse, Y., Endo, Y., Araoi, S., Daitoku, H., Suzuki, H., Kato, M., Kobayashi, M. (2017) The possible repositioning of an oral anti-arthritic drug, auranofin, for Nrf2-activating therapy: the demonstration of Nrf2-dependent anti-oxidative action using a zebrafish model. Free radical biology & medicine. 115:405-411.
Abstract
The Nrf2 pathway is a biological defense system against oxidative stress. The pharmacological activation of the Nrf2 pathway is a promising therapy for oxidative stress-related diseases, but it has been challenging to find an Nrf2 activator with acceptable toxicity. To circumvent this problem, we focused on an already approved oral anti-arthritic drug, auranofin that has been reported to have the potential to activate Nrf2. We used a zebrafish model to investigate whether auranofin has protective action against oxidative stress in vivo. Auranofin pre-treatment considerably improved the survival of zebrafish larvae that were challenged with a lethal dose of hydrogen peroxide. This protective effect was not observed in an Nrf2 mutant zebrafish strain, suggesting that the activation of the biological defense against oxidative stress was Nrf2-dependent. Auranofin-induced protection was further tested by challenges with redox-active heavy metals. A clear protective effect was observed against arsenite, a highly redox-reactive toxicant. In addition, this effect was also demonstrated to be Nrf2-dependent based on the analysis of an Nrf2 mutant strain. These results clearly demonstrate the anti-oxidative action of auranofin and encourage the repositioning of auranofin as a drug that improves oxidative stress-related pathology.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping