A synthetic triterpenoid, CDDO-Me, inhibits IkappaBalpha kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappaB-regulated gene products in human leukemic cells.

Abstract

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 kappaB (NF-kappaB) has been shown to suppress apoptosis and promote proliferation and is linked with inflammation and differentiation, we postulated that CDDO-Me modulates NF-kappaB activity and NF-kappaB-regulated gene expression. Using human leukemia cell lines and patient samples, we show that CDDO-Me potently inhibits both constitutive and inducible NF-kappaB activated by tumor necrosis factor (TNF), interleukin (IL)-1beta, phorbol ester, okadaic acid, hydrogen peroxide, lipopolysaccharide, and cigarette smoke. CDDO-Me was more potent than CDDO and its imidazole derivative. NF-kappaB suppression occurred through inhibition of IkappaBalpha kinase activation, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and NF-kappaB-mediated reporter gene transcription. This inhibition correlated with suppression of NF-kappaB-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-kappaB through inhibition of IkappaBalpha kinase, leading to the suppression of expression of NF-kappaB-regulated gene products and enhancement of apoptosis induced by TNF and chemotherapeutic agents.

• Authors: Shishir Shishodia, Gautam Sethi, Marina Konopleva, Michael Andreeff, Bharat B Aggarwal
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 6 Pg. 1828-38 (Mar 15 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16551868 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
• 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
• Antineoplastic Agents
• Imidazoles
• NF-kappa B
• Receptors, Tumor Necrosis Factor
• Recombinant Fusion Proteins
• TNF Receptor-Associated Death Domain Protein
• Triterpenes
• Tumor Necrosis Factors
• Oleanolic Acid
• bardoxolone methyl
• Cyclooxygenase 2
• I-kappa B Kinase
• Matrix Metalloproteinase 9

Topics

• Active Transport, Cell Nucleus (drug effects)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Nucleus (genetics, metabolism)
• Cell Survival (drug effects)
• Cyclooxygenase 2 (genetics, metabolism)
• Gene Expression (drug effects)
• Humans
• I-kappa B Kinase (antagonists & inhibitors, metabolism)
• Imidazoles (pharmacology)
• Leukemia (genetics, metabolism, pathology)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Oleanolic Acid (analogs & derivatives, chemistry, pharmacology)
• Phosphorylation (drug effects)
• Promoter Regions, Genetic (genetics)
• Receptors, Tumor Necrosis Factor (metabolism)
• Recombinant Fusion Proteins (genetics, metabolism)
• TNF Receptor-Associated Death Domain Protein (metabolism)
• Triterpenes (chemistry, pharmacology)
• Tumor Necrosis Factors (pharmacology)
• U937 Cells