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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

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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

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_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16551868 DB - PRIME DP - Unbound Medicine ER -