This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shishodia, S. Articles by Aggarwal, B. B. Search for Related Content PubMed PubMed Citation Articles by Shishodia, S. Articles by Aggarwal, B. B.

A Synthetic Triterpenoid, CDDO-Me, Inhibits IB Kinase and Enhances Apoptosis Induced by TNF and Chemotherapeutic Agents through Down-Regulation of Expression of Nuclear Factor B–Regulated Gene Products in Human Leukemic Cells

Authors' Affiliations: ¹ Cytokine Research Laboratory, Department of Experimental Therapeutics and ² Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Bharat B. Aggarwal, Department of Experimental Therapeutics, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 143, Houston, TX 77030. Phone: 713-792-3503/6459; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org.

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

This article has been cited by other articles:

				W. Zou, P. Yue, F. R. Khuri, and S.-Y. Sun Coupling of Endoplasmic Reticulum Stress to CDDO-Me-Induced Up-regulation of Death Receptor 5 via a CHOP-Dependent Mechanism Involving JNK Activation Cancer Res., September 15, 2008; 68(18): 7484 - 7492. [Abstract] [Full Text] [PDF]

				R. Vene, P. Larghero, G. Arena, M. B. Sporn, A. Albini, and F. Tosetti Glycogen Synthase Kinase 3{beta} Regulates Cell Death Induced by Synthetic Triterpenoids Cancer Res., September 1, 2008; 68(17): 6987 - 6996. [Abstract] [Full Text] [PDF]

				D. Zhang, X. Jin, F. Wang, S. Wang, C. Deng, Z. Gao, and C. Guo Combined Prognostic Value of Both RelA and I{kappa}B-{alpha} Expression in Human Non Small Cell Lung Cancer Ann. Surg. Oncol., December 1, 2007; 14(12): 3581 - 3592. [Abstract] [Full Text] [PDF]

				S. Koschmieder, F. D'Alo, H. Radomska, C. Schoneich, J. S. Chang, M. Konopleva, S. Kobayashi, E. Levantini, N. Suh, A. Di Ruscio, et al. CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha Blood, November 15, 2007; 110(10): 3695 - 3705. [Abstract] [Full Text] [PDF]

				X. Ling, M. Konopleva, Z. Zeng, V. Ruvolo, L. C. Stephens, W. Schober, T. McQueen, M. Dietrich, T. L. Madden, and M. Andreeff The Novel Triterpenoid C-28 Methyl Ester of 2-Cyano-3, 12-Dioxoolen-1, 9-Dien-28-Oic Acid Inhibits Metastatic Murine Breast Tumor Growth through Inactivation of STAT3 Signaling Cancer Res., May 1, 2007; 67(9): 4210 - 4218. [Abstract] [Full Text] [PDF]

				M. S. Yates, M. Tauchi, F. Katsuoka, K. C. Flanders, K. T. Liby, T. Honda, G. W. Gribble, D. A. Johnson, J. A. Johnson, N. C. Burton, et al. Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes Mol. Cancer Ther., January 1, 2007; 6(1): 154 - 162. [Abstract] [Full Text] [PDF]

				M. M. Yore, K. T. Liby, T. Honda, G. W. Gribble, and M. B. Sporn The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-{kappa}B activation through direct inhibition of I{kappa}B kinase {beta} Mol. Cancer Ther., December 1, 2006; 5(12): 3232 - 3239. [Abstract] [Full Text] [PDF]

				R. Ahmad, D. Raina, C. Meyer, S. Kharbanda, and D. Kufe Triterpenoid CDDO-Me Blocks the NF-{kappa}B Pathway by Direct Inhibition of IKKbeta on Cys-179 J. Biol. Chem., November 24, 2006; 281(47): 35764 - 35769. [Abstract] [Full Text] [PDF]