Methyl 2-cyano-3,11-dioxo-18-olean-1,12-dien-30-oate (
CDODA-Me), a
triterpenoid acid derived synthetically from
glycyrrhetinic acid, has been characterized as a
peroxisome proliferator-activated receptor γ agonist with a broad range of receptor-dependent and -independent anticancer activities. Although
CDODA-Me decreases the expression of some angiogenic genes in
cancer cells, the direct effects of this compound on angiogenesis have not been defined. In this study, we have extensively investigated the activities of
CDODA-Me in multiple angiogenesis assays. Our results showed that this agent inhibited
vascular endothelial growth factor (
VEGF)-induced proliferation, migration, invasion, and lamellipodium and capillary-like structure formation of human umbilical endothelial cells (HUVECs) in a concentration-dependent manner. Moreover,
CDODA-Me abrogated
VEGF-induced sprouting of microvessels from rat aortic rings ex vivo and inhibited the generation of new vasculature in the
Matrigel plugs in vivo, where
CDODA-Me significantly decreased the number of infiltrating
von Willebrand factor-positive endothelial cells. To understand the molecular basis of this antiangiogenic activity, we examined the signaling pathways in
CDODA-Me-treated HUVECs. Our results showed that
CDODA-Me significantly suppressed the activation of
VEGF receptor 2 (VEGFR2) and interfered with the
mammalian target of rapamycin (mTOR) signaling, including mTOR
kinase and its downstream ribosomal
S6 kinase (S6K), but had little effect on the activities of extracellular signal-regulated
protein kinase and AKT. Taken together,
CDODA-Me blocks several key steps of angiogenesis by inhibiting
VEGF/VEGFR2 and mTOR/S6K signaling pathways, making the compound a promising agent for the treatment of
cancer and angiogenesis-related pathologies.