%0 Journal Article %A Shishodia, Shishir %A Sethi, Gautam %A Konopleva, Marina %A Andreeff, Michael %A Aggarwal, Bharat B. %T A Synthetic Triterpenoid, CDDO-Me, Inhibits IκBα Kinase and Enhances Apoptosis Induced by TNF and Chemotherapeutic Agents through Down-Regulation of Expression of Nuclear Factor κB–Regulated Gene Products in Human Leukemic Cells %D 2006 %R 10.1158/1078-0432.CCR-05-2044 %J Clinical Cancer Research %P 1828-1838 %V 12 %N 6 %X The C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO-Me), a synthetic triterpenoid based on naturally occurring ursolic and oleanolic acids, induces apoptosis in tumor cells, induces differentiation, and inhibits inflammatory response through a poorly understood mechanism. Because the nuclear transcription factor nuclear factor κB (NF-κB) has been shown to suppress apoptosis and promote proliferation and is linked with inflammation and differentiation, we postulated that CDDO-Me modulates NF-κB activity and NF-κB-regulated gene expression. Using human leukemia cell lines and patient samples, we show that CDDO-Me potently inhibits both constitutive and inducible NF-κB activated by tumor necrosis factor (TNF), interleukin (IL)-1β, phorbol ester, okadaic acid, hydrogen peroxide, lipopolysaccharide, and cigarette smoke. CDDO-Me was more potent than CDDO and its imidazole derivative. NF-κB suppression occurred through inhibition of IκBα kinase activation, IκBα phosphorylation, IκBα degradation, p65 phosphorylation, p65 nuclear translocation, and NF-κB-mediated reporter gene transcription. This inhibition correlated with suppression of NF-κB-dependent genes involved in antiapoptosis (IAP2, cFLIP, TRAF1, survivin, and bcl-2), proliferation (cyclin d1 and c-myc), and angiogenesis (VEGF, cox-2, and mmp-9). CDDO-Me also potentiated the cytotoxic effects of TNF and chemotherapeutic agents. Overall, our results suggest that CDDO-Me inhibits NF-κB through inhibition of IκBα kinase, leading to the suppression of expression of NF-κB-regulated gene products and enhancement of apoptosis induced by TNF and chemotherapeutic agents. %U https://clincancerres.aacrjournals.org/content/clincanres/12/6/1828.full.pdf