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Departments of Pharmacology (Y.W., N.S., M.B.S.) and Chemistry
(T.H., G.W.G.) Dartmouth Medical School and Dartmouth College
Hanover, New Hampshire 03755
Howard Hughes Medical Institute
and Departments of Pharmacology and Biochemistry (W.W.P., D.J.M)
University of Texas Southwestern Medical Center Dallas, Texas
75390
Departments of Molecular Biochemistry (L.M.L., S.G.B.),
Molecular Endocrinology (K.D.P.), and Medicinal Chemistry (T.M.W.)
Glaxo Wellcome Research and Development Research Triangle Park,
North Carolina 27709
A novel synthetic triterpenoid,
2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), previously
reported to have potent differentiating, antiproliferative, and
antiinflammatory activities, has been identified as a ligand for the
peroxisome proliferator-activated receptor 
(PPAR). CDDO induces
adipocytic differentiation in 3T3-L1 cells, although it is not as
potent as the full agonist of PPAR, rosiglitazone. Binding studies
of CDDO to PPAR using a scintillation proximity assay give a
Ki between 10-8 to
10-7 M. In
transactivation assays, CDDO is a partial agonist for PPAR. The
methyl ester of CDDO, CDDO-Me, binds to PPAR with similar affinity,
but is an antagonist. Like other PPAR ligands, CDDO synergizes with
a retinoid X receptor (RXR)-specific ligand to induce 3T3-L1
differentiation, while CDDO-Me is an antagonist in this assay. The
partial agonism of CDDO and the antagonism of CDDO-Me reflect the
differences in their capacity to recruit or displace cofactors of
transcriptional regulation; CDDO and rosiglitazone both release the
nuclear receptor corepressor, NCoR, from PPAR, while CDDO-Me does
not. The differences between CDDO and rosiglitazone as either partial
or full agonists, respectively, are seen in the weaker ability of CDDO
to recruit the coactivator CREB-binding protein, CBP, to PPAR. Our
results establish the triterpenoid CDDO as a member of a new class of
PPAR ligands.
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G. Lee, F. Elwood, J. McNally, J. Weiszmann, M. Lindstrom, K. Amaral, M. Nakamura, S. Miao, P. Cao, R. M. Learned, et al. T0070907, a Selective Ligand for Peroxisome Proliferator-activated Receptor gamma , Functions as an Antagonist of Biochemical and Cellular Activities J. Biol. Chem., May 24, 2002; 277(22): 19649 - 19657. [Abstract] [Full Text] [PDF]
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T. A. Stadheim, N. Suh, N. Ganju, M. B. Sporn, and A. Eastman The Novel Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) Potently Enhances Apoptosis Induced by Tumor Necrosis Factor in Human Leukemia Cells J. Biol. Chem., May 3, 2002; 277(19): 16448 - 16455. [Abstract] [Full Text] [PDF]
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K. B. Kim, R. Lotan, P. Yue, M. B. Sporn, N. Suh, G. W. Gribble, T. Honda, G. S. Wu, W. K. Hong, and S.-Y. Sun Identification of a Novel Synthetic Triterpenoid, Methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate, That Potently Induces Caspase-mediated Apoptosis in Human Lung Cancer Cells Mol. Cancer Ther., January 1, 2002; 1(3): 177 - 184. [Abstract] [Full Text] [PDF]
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M. Konopleva, T. Tsao, P. Ruvolo, I. Stiouf, Z. Estrov, C. E. Leysath, S. Zhao, D. Harris, S. Chang, C. E. Jackson, et al. Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia Blood, January 1, 2002; 99(1): 326 - 335. [Abstract] [Full Text] [PDF]
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