Abstract
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.
Footnotes
This work is supported by the Research Platform for Cell Signaling Networks [Grant 06DZ22923], the Science and Technology Commission of Shanghai Municipality [Grant 09PJ1403900], and the National Institutes of Health National Cancer Institute [Grant R01-CA106479] (to M.L.). S.S. was supported by the National Institutes of Health National Cancer Institute [Grant R01-CA136571]. X.P. was supported by East China Normal University [Grant 78210021].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.171066.
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ABBREVIATIONS:
- CDODA-Me
- methyl 2-cyano-3,11-dioxo-18-olean-1,12-dien-30-oate
- VEGF
- vascular endothelial growth factor
- VEGFR
- VEGF receptor
- HUVEC
- human umbilical endothelial cell
- PPARγ
- peroxisome proliferator-activated receptor γ
- mTOR
- mammalian target of rapamycin
- ERK
- extracellular signal-regulated protein kinase
- ECGM
- endothelial cell growth medium
- FBS
- fetal bovine serum
- vWF
- von Willebrand factor
- BrdU
- 5′-bromo-2′-deoxyuridine
- MTS
- 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
- S6K
- S6 kinase
- Sp
- specificity protein
- PARP
- poly(ADP-ribose) polymerase.
- Received June 3, 2010.
- Accepted July 14, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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