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Clinical Cancer Research Vol. 9, 2798-2806, July 2003
© 2003 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

The Novel Synthetic Triterpenoid, CDDO-Imidazolide, Inhibits Inflammatory Response and Tumor Growth in Vivo1

Andrew E. Place2, Nanjoo Suh2, Charlotte R. Williams, Renee Risingsong, Tadashi Honda, Yukiko Honda, Gordon W. Gribble, Lisa M. Leesnitzer, Julie B. Stimmel, Timothy M. Willson, Evan Rosen and Michael B. Sporn3

Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03755 [A. E. P., N. S., C. R. W., R. R., M. B. S.]; Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755 [T. H., Y. H., G. W. G.]; Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709 [L. M. L., J. B. S., T. M. W.]; and Department of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215 [E. R.]

1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) is a novel synthetic triterpenoid more potent than its parent compound, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), both in vitro and in vivo. CDDO-Im is highly active in suppressing cellular proliferation of human leukemia and breast cancer cell lines (IC50, ~10–30 nM). In U937 leukemia cells, CDDO-Im also induces monocytic differentiation as measured by increased cell surface expression of CD11b and CD36. In each of these assays, CDDO-Im is several-fold more active than CDDO. Although CDDO and CDDO-Im both bind and transactivate peroxisome proliferator-activated receptor (PPAR) {gamma}, the irreversible PPAR{gamma} antagonist GW9662 does not block the ability of either CDDO or CDDO-Im to induce differentiation; moreover, PPAR{gamma}-null fibroblasts are still sensitive to the growth-suppressive effects of CDDO. Thus, CDDO-Im has significant actions independent of PPAR{gamma} transactivation. In addition, the rexinoid LG100268 and the deltanoid ILX23-7553 (ILX7553) synergize with CDDO and CDDO-Im to induce differentiation. In vivo, CDDO-Im is a potent inhibitor of de novo inducible nitric oxide synthase expression in primary mouse macrophages. Moreover, CDDO-Im inhibits growth of B16 murine melanoma and L1210 murine leukemia cells in vivo. The potent effects of CDDO-Im, both in vitro and in vivo, suggest it should be considered for clinical use.




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