The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivo.

Abstract

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 (IC(50), approximately 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 PPARgamma antagonist GW9662 does not block the ability of either CDDO or CDDO-Im to induce differentiation; moreover, PPARgamma-null fibroblasts are still sensitive to the growth-suppressive effects of CDDO. Thus, CDDO-Im has significant actions independent of PPARgamma 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.