ZFIN ID: ZDB-PUB-171227-1
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
Fuse, Y., Endo, Y., Araoi, S., Daitoku, H., Suzuki, H., Kato, M., Kobayashi, M.
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:
  • Administration, Oral
  • Animals
  • Antioxidants/pharmacology
  • Antioxidants/therapeutic use*
  • Antirheumatic Agents/pharmacology
  • Antirheumatic Agents/therapeutic use*
  • Arsenites/toxicity
  • Arthritis/drug therapy*
  • Auranofin/pharmacology
  • Auranofin/therapeutic use*
  • Disease Models, Animal
  • Drug Repositioning
  • Humans
  • Hydrogen Peroxide/toxicity
  • Larva
  • Metals, Heavy/toxicity
  • Mutation/genetics
  • NF-E2-Related Factor 2/antagonists & inhibitors*
  • NF-E2-Related Factor 2/genetics
  • Organisms, Genetically Modified
  • Oxidation-Reduction
  • Oxidative Stress/drug effects
  • Signal Transduction
  • Zebrafish
  • Zebrafish Proteins/antagonists & inhibitors*
  • Zebrafish Proteins/genetics
PubMed: 29277393 Full text @ Free Radic. Biol. Med.
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.
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