Triterpenoid CDDO-Me blocks the NF-κB pathway by direct inhibition of IKKβ on Cys-179

The novel oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid ( CDDO) and the C-28 methyl ester (CDDO-Me) induce apoptosis of human tumor cells by disruption of redox balance and are currently in clinical trials. The present studies show that CDDO and CDDO-Me block tumor necrosis factor alpha-induced targeting of NF-kappa B p65 to the nucleus. CDDO- Me also blocked tumor necrosis factor alpha-induced phosphorylation of I kappa B alpha. In concert with these results, we found that CDDO- Me inhibits I kappa B alpha kinase beta(IKK beta) activity in cells. In support of a direct mechanism, CDDO- Me inhibited recombinant IKK beta activity in vitro. The results also demonstrate that (i) CDDO and CDDO- Me form adducts with IKK beta, but not IKK beta with mutation of Cys-179 to Ala, and (ii)CDDO- Me inhibits IKK beta by a mechanism dependent on oxidation of Cys-179. These findings indicate that CDDO and CDDO-Me directly block IKK beta activity and thereby the NF-kappa B pathway by interacting with Cys-179 in the IKK beta activation loop.