Carboxyamido-triazole inhibits angiogenesis by blocking the calcium-mediated nitric-oxide synthase-vascular endothelial growth factor pathway
| Autor: | K S, Bauer, K J, Cude, S C, Dixon, E A, Kruger, W D, Figg |
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| Rok vydání: | 1999 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Lymphokines Dose-Response Relationship Drug Neovascularization Pathologic Vascular Endothelial Growth Factors Microcirculation Aorta Thoracic Endothelial Growth Factors In Vitro Techniques Triazoles Calcium Channel Blockers Rats Rats Sprague-Dawley Animals Humans Endothelium Vascular Nitric Oxide Synthase Cell Division Cells Cultured |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 292(1) |
| ISSN: | 0022-3565 |
| Popis: | The induction of angiogenesis is known to play a critical role in the successful growth, invasion, and metastasis of a tumor. A tumor will not grow beyond a few cubic millimeters without the formation of its own capillary network. Several antiangiogenic agents are under investigation in the clinic setting for the treatment of cancer. Carboxyamido-triazole (CAI), an inhibitor of Ca(2+)-mediated signal transduction, has been previously shown to inhibit angiogenesis in vitro and in vivo and to down-regulate matrix metalloproteinase-2 in vitro. Diminished levels of intracellular Ca(2+) result in decreased nitric-oxide synthase (NOS) activity and thereby inhibit the production and release of NO. The antiangiogenic activity of CAI was investigated by assessing microvessel growth from rat aortic segments and in cell culture using human aortic endothelial cells (HAECs). With these models, vascular endothelial growth factor (VEGF) and NOS production and secretion were evaluated. CAI concentrations ranging from 0.25 to 12.0 microg/ml inhibited new microvessel formation in rat aortic cultures and HAEC proliferation in a dose-dependent manner. Additionally, HAECs treated with CAI showed a dose-dependent decrease of NOS expression and a decrease in both VEGF expression and secretion. Rat aortic segments demonstrated decreased VEGF expression in situ on immunostaining. These data suggest that modulation of the NOS-NO-VEGF pathway through Ca(2+)-mediated signaling by CAI inhibits angiogenesis in vitro. |
| Databáze: | OpenAIRE |
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