Constitutive and Inducible Nuclear Factor-B (NF-B) Activation by Modifying p65 on Cysteine 38 Residue and Reducing Inhibitor of Nuclear Factor-B Kinase Activation, Leading to Suppression of NF-B-Regulated Gene Expression and Sensitization of Tumor Cells

Abstract

Although inflammatory pathways have been linked with various chronic diseases including cancer, identification of an agent that can suppress these pathways has therapeutic potential. Herein we describe the identification of a novel compound bharangin, a diterpenoid quinonemethide that can suppress pro-inflammatory pathways specifically. We found that bha-rangin suppresses nuclear factor (NF)-B activation induced by pro-inflammatory cytokine, tumor promoter, cigarette smoke, and endotoxin. Inhibition of NF-B activation was mediated through the suppression of phosphorylation and degradation of inhibitor of nuclear factor-B (IB); inhibition of IB kinase activation; and suppression of p65 nuclear translocation, and phosphorylation. The diterpenoid inhibited binding of p65 to DNA. A reducing agent reversed the inhibitory effect, and mu