Chemopreventive promise of targeting the Nrf2 pathway.
The Kelch ECH associating protein 1-nuclear factor-E2-related factor 2-antioxidant response element (Keap 1-Nrf2-ARE) signaling pathway regulates several protective mechanisms including expression of conjugating and antioxidative genes, antiinflammatory responses, the molecular chaperone/stress response system and the ubiquitin/proteasome system. The Nrf2-mediated response alters susceptibility to carcinogenesis, acute chemical toxicity, oxidative stress, asthma, acute inflammation, septic shock and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Studies using natural and synthetic chemical inducers that activate Nrf2 signaling have demonstrated protective efficacy in many animal models of disease. Conversely, studies in Nrf2-disrupted mice indicate they exhibit increased sensitivity to many of these diseases. Thus, activation of Keap1-Nrf2-ARE signaling constitutes a broad protective response, making Nrf2 and its interacting partners important targets for chemoprevention. However, additional studies are needed to characterize Keap1-Nrf2-ARE signaling in humans to further develop exceptionally potent activators of the pathway and further understand the potential consequences of altering this system.
Yates
Melinda S
MS
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Kensler
Thomas W
TW
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D061745:Antioxidant Response Elements; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015195:Drug Design; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D058990:Molecular Targeted Therapy; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects*
D016588:Anticarcinogenic Agents; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2