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Carboxyamido-triazole inhibits angiogenesis by blocking the calcium-mediated nitric-oxide synthase-vascular
K S Bauer1, K J Cude, S C Dixon
1Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
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.
Insights
Carboxyamido-triazole (CAI) inhibits angiogenesis, the formation of new blood vessels essential for tumor growth. This compound reduces nitric-oxide synthase (NOS) and vascular endothelial growth factor (VEGF) production, key factors in angiogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Tumor growth, invasion, and metastasis are critically dependent on angiogenesis.
- Tumors require a capillary network to grow beyond a minimal size.
- Antiangiogenic agents are being investigated for cancer treatment.
Purpose of the Study:
- To investigate the antiangiogenic activity of Carboxyamido-triazole (CAI).
- To evaluate the effect of CAI on nitric-oxide synthase (NOS) and vascular endothelial growth factor (VEGF) pathways.
- To assess CAI's impact on microvessel formation and endothelial cell proliferation.
Main Methods:
- Assessed microvessel growth from rat aortic segments in vitro.
- Utilized human aortic endothelial cells (HAECs) in cell culture.
- Measured NOS and VEGF production, secretion, and expression.
- Evaluated CAI's dose-dependent effects on angiogenesis and cell proliferation.
Main Results:
- CAI inhibited new microvessel formation in rat aortic cultures and HAEC proliferation in a dose-dependent manner.
- CAI treatment decreased NOS expression in HAECs.
- CAI reduced both VEGF expression and secretion in HAECs and in situ in rat aortic segments.
Conclusions:
- CAI effectively inhibits angiogenesis in vitro.
- CAI's mechanism involves the modulation of the NOS-NO-VEGF pathway.
- CAI demonstrates potential as an antiangiogenic agent by targeting Ca(2+)-mediated signaling.