The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivo.
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.
Place
Andrew E
AE
Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Suh
Nanjoo
N
Williams
Charlotte R
CR
Risingsong
Renee
R
Honda
Tadashi
T
Honda
Yukiko
Y
Gribble
Gordon W
GW
Leesnitzer
Lisa M
LM
Stimmel
Julie B
JB
Willson
Timothy M
TM
Rosen
Evan
E
Sporn
Michael B
MB
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D039481:CD11b Antigen / Q000096:biosynthesis; D018955:CD36 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation; D002455:Cell Division; D045744:Cell Line, Tumor; D002469:Cell Separation; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D009000:Monocytes / Q000166:cytology; D009369:Neoplasms / Q000188:drug therapy; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D020298:U937 Cells
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D000970:Antineoplastic Agents; D039481:CD11b Antigen; D018955:CD36 Antigens; C428283:ILX237553; D007093:Imidazoles; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D002762:Cholecalciferol; D009828:Oleanolic Acid; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse