The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent antiangiogenic agent.
We show that the synthetic oleanane triterpenoid, CDDO-methyl ester (CDDO-Me; methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate) is an effective agent for suppressing angiogenesis, both in cell culture and in vivo. The potency of CDDO-Me is particularly striking when dosed in vivo to inhibit the angiogenic effects of vascular endothelial growth factor and tumor necrosis factor-alpha in Matrigel sponge assays; activity is seen at i.p. doses of CDDO-Me as low as 0.003 mg/kg of body weight. If the Matrigel sponges are impregnated with CDDO-Me just before implantation in the mice, picomolar doses of CDDO-Me will suppress angiogenesis. CDDO-Me also inhibits growth of endothelial cells in monolayer cultures and suppresses neovascular morphogenesis in three-dimensional cultures, but significantly higher doses (50-200 nmol/L) are required. We also show antiangiogenic effects of CDDO-Me on xenografts of Kaposi's sarcoma cells in immunocompromised mice, using CD31 as a marker. Several known individual molecular targets of CDDO-Me and related triterpenoids that are relevant to all of these findings include nuclear factor-kappaB signaling, signal transducers and activators of transcription signaling, and transforming growth factor-beta signaling, as well as Keap1, the endogenous inhibitor of the transcription factor Nrf2. However, the particularly potent antiangiogenic activity seen in vivo in the present experiments suggest that CDDO-Me, as an angioprevention agent, may be interacting with an entire network of molecular and cellular targets, rather than at a single molecular locus or in a single-cell type.
Multimedica IRCCS, Milan, Italy.
Nicola
N
Vannini
Girieca
G
Lorusso
Rosaria
R
Cammarota
Massimo
M
Barberis
Douglas M
DM
Noonan
Michael B
MB
Sporn
Adriana
A
Albini
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen; D004338:Drug Combinations; D006801:Humans; D007797:Laminin; D051379:Mice; D009369:Neoplasms / Q000098:blood supply; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011509:Proteoglycans; D012514:Sarcoma, Kaposi / Q000473:pathology
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D009828:Oleanolic Acid; D003094:Collagen; C445068:bardoxolone methyl