Methyl 2-cyano-3,11-dioxo-18-olean-1,12-dien-30-oate (CDODA-Me), a derivative of glycyrrhetinic acid, functions as a potent angiogenesis inhibitor.
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.
Pang
Xiufeng
X
Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Zhang
Li
L
Wu
Yougen
Y
Lin
Lei
L
Li
Jingjie
J
Qu
Weijing
W
Safe
Stephen
S
Liu
Mingyao
M
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002196:Capillaries / Q000187:drug effects / Q000502:physiology; D020169:Caspases / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
D020533:Angiogenesis Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C543611:methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-dien-30-oate; C546842:MTOR protein, human; C546845:mTOR protein, rat; D040262:Receptors, Vascular Endothelial Growth Factor; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases; D006034:Glycyrrhetinic Acid