title: Toward an understanding of the role of a catechol moiety in cancer chemoprevention: The case of copper- and o-quinone-dependent Nrf2 activation by a catechol-type resveratrol analog.
abstract: METHODS
  Catechol moieties are commonly present in dietary natural products that exert cancer chemopreventive activity. While the oxidative conversion of catechols into their corresponding o-quinones is generally considered to contribute to their cancer chemopreventive effects, the mechanism of the intracellular conversion has not been fully elucidated.
  
  
  RESULTS
  Among resveratrol and its hydroxylated analogs examined, only 3,4-dihydroxy-trans-stilbene exerted cytoprotective effects against t-butylhydroperoxide-induced death of HepG2 cells. This resveratrol analog activated the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway through stimulating phosphorylation of Akt and inducing keap1 modification, thereby resulting in its nuclear translocation and subsequent transcriptional induction of phase II detoxifying enzymes. Its cytoprotective effect through Nrf2 activation was largely abrogated by pretreatment of cells with DTT, a sulfhydryl-containing nucleophile, and neocuproine, a specific chelating agent for copper ions.
  
  
  CONCLUSIONS
  We identified 3,4-dihydroxy-trans-stilbene as a novel Nrf2 activator that is converted intracellularly into its corresponding o-quinone electrophile by copper ions. The copper-mediated oxidation was required for the Nrf2 activation, subsequent transcriptional induction of phase II detoxifying enzymes and ultimately for cytoprotection. The findings demonstrate a previously underrecognized role for intracellular copper ions in the cancer chemopreventive effects of catechol-containing dietary natural products.
authors: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu, P. R. China.
authors: Dong
authors: D
authors: Lin
authors: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu, P. R. China.
authors: Fang
authors: F
authors: Dai
authors: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu, P. R. China.
authors: Lan-Di
authors: LD
authors: Sun
authors: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu, P. R. China.
authors: Bo
authors: B
authors: Zhou
mesh_terms: D016588:Anticarcinogenic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002396:Catechols / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000378:metabolism*; D056945:Hep G2 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C578987:3,4'-dihydroxystilbene; D016588:Anticarcinogenic Agents; D002396:Catechols; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D013267:Stilbenes; D003300:Copper; D051057:Proto-Oncogene Proteins c-akt; C034221:catechol; D000077185:Resveratrol
keywords: Cancer chemoprevention; Copper; Nrf2 / o-Quinone; Resveratrol