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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.
Clin Cancer Res. 2006 Mar 15; 12(6):1828-38.CC

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+Show Affiliations

Shishodia S
Cytokine Research Laboratory, Department of Experimental Therapeutics, Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Sethi G
No affiliation info available
Konopleva M
No affiliation info available
Andreeff M
No affiliation info available
Aggarwal BB
No affiliation info available

MeSH

Active Transport, Cell NucleusAntineoplastic AgentsApoptosisCell Line, TumorCell NucleusCell SurvivalCyclooxygenase 2Gene ExpressionHumansI-kappa B KinaseImidazolesLeukemiaMatrix Metalloproteinase 9NF-kappa BOleanolic AcidPhosphorylationPromoter Regions, GeneticReceptors, Tumor Necrosis FactorRecombinant Fusion ProteinsTNF Receptor-Associated Death Domain ProteinTriterpenesTumor Necrosis FactorsU937 Cells

Pub Type(s)

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.

Language

eng

PubMed ID

16551868

Clinical Trial Links

Effect of Sulforaphane in Broccoli Sprouts on Nrf2 Activation

Citation

Shishodia, Shishir, et al. "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." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 12, no. 6, 2006, pp. 1828-38.
Shishodia S, Sethi G, Konopleva M, et al. 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. Clin Cancer Res. 2006;12(6):1828-38.
Shishodia, S., Sethi, G., Konopleva, M., Andreeff, M., & Aggarwal, B. B. (2006). 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. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 12(6), 1828-38.
Shishodia S, et al. 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. Clin Cancer Res. 2006 Mar 15;12(6):1828-38. PubMed PMID: 16551868.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Shishodia,Shishir, AU - Sethi,Gautam, AU - Konopleva,Marina, AU - Andreeff,Michael, AU - Aggarwal,Bharat B, PY - 2006/3/23/pubmed PY - 2006/12/9/medline PY - 2006/3/23/entrez SP - 1828 EP - 38 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 12 IS - 6 N2 - 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. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/16551868/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_ DB - PRIME DP - Unbound Medicine ER -
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