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.

SCOPE: 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.

METHODS AND 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.

CONCLUSION: 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.