Cinnamoyl-based Nrf2-activators targeting human skin cell photo-oxidative stress.
Strong experimental evidence suggests the involvement of photo-oxidative stress mediated by reactive oxygen species as a crucial mechanism of solar damage relevant to human skin photoaging and photocarcinogenesis. Based on the established role of antioxidant response element (ARE)-mediated gene expression in cancer chemoprevention, we tested the hypothesis that small molecule Nrf2-activators may serve a photo-chemopreventive role by targeting skin cell photo-oxidative stress. A luciferase-based reporter gene assay was used as a primary screen for the identification of novel agents that modulate the Nrf2-Keap1 signaling pathway. A series of cinnamoyl-based electrophilic Michael acceptors including cinnamic aldehyde and methyl-1-cinnamoyl-5-oxo-2-pyrrolidine-carboxylate was identified as potent Nrf2-activators. Hit confirmation was performed in a secondary screen, based on immunodetection of Nrf2 protein upregulation in human Hs27 skin fibroblasts, HaCaT keratinocytes, and primary skin keratinocytes. Bioefficacy profiling of positive test compounds in skin cells demonstrated compound-induced upregulation of hemeoxygenase I and NAD(P)H-quinone oxidoreductase, two Nrf2 target genes involved in the cellular antioxidant response. Pretreatment with cinnamoyl-based Nrf2-activators suppressed intracellular oxidative stress and protected against photo-oxidative induction of apoptosis in skin cells exposed to high doses of singlet oxygen. Our pilot studies suggest feasibility of developing cinnamoyl-based Nrf2-activators as novel photo-chemopreventive agents targeting skin cell photo-oxidative stress.
Wondrak
Georg T
GT
Department of Pharmacology and Toxicology, College of Pharmacy, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA. wondrak@pharmacy.arizona.edu
Cabello
Christopher M
CM
Villeneuve
Nicole F
NF
Zhang
Shirley
S
Ley
Stephanie
S
Li
Yanjie
Y
Sun
Zheng
Z
Zhang
Donna D
DD
D000171:Acrolein / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D006801:Humans; D008027:Light; D051267:NF-E2-Related Factor 2 / Q000819:agonists*; D018384:Oxidative Stress; D012867:Skin / Q000187:drug effects* / Q000528:radiation effects
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000171:Acrolein; C012843:cinnamaldehyde