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.

• Authors: Andrew E Place, Nanjoo Suh, Charlotte R Williams, Renee Risingsong, Tadashi Honda, Yukiko Honda, Gordon W Gribble, Lisa M Leesnitzer, Julie B Stimmel, Timothy M Willson, Evan Rosen, Michael B Sporn
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 7 Pg. 2798-806 (Jul 2003) ISSN: 1078-0432 [Print] United States
• PMID: 12855660 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
• 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
• Antineoplastic Agents
• CD11b Antigen
• CD36 Antigens
• ILX237553
• Imidazoles
• Receptors, Cytoplasmic and Nuclear
• Transcription Factors
• Cholecalciferol
• Oleanolic Acid
• NOS2 protein, human
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• CD11b Antigen (biosynthesis)
• CD36 Antigens (biosynthesis)
• Cell Differentiation
• Cell Division
• Cell Line, Tumor
• Cell Separation
• Cholecalciferol (analogs & derivatives, pharmacology)
• Dose-Response Relationship, Drug
• Female
• Fibroblasts (metabolism)
• Flow Cytometry
• Humans
• Imidazoles (pharmacology)
• Inflammation
• Inhibitory Concentration 50
• Mice
• Models, Chemical
• Monocytes (cytology)
• Neoplasms (drug therapy)
• Nitric Oxide Synthase (metabolism)
• Nitric Oxide Synthase Type II
• Oleanolic Acid (analogs & derivatives, pharmacology)
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Time Factors
• Transcription Factors (metabolism)
• Transcriptional Activation
• U937 Cells