Carboxyamido-triazole inhibits angiogenesis by blocking the calcium-mediated nitric-oxide synthase-vascular endothelial growth factor pathway

作     者：Bauer, KS Cude, KJ Dixon, SC Kruger, EA Figg, WD 

作者机构：NCI Div Clin Sci Med Branch NIH Bethesda MD 20892 USA 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：2000年第292卷第1期

页      面：31-37页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：National Cancer Institute  NCI  (Z01SC006538) 

主　　题：主动脉 胸/生理学 钙通道阻滞药/药理学 细胞分裂/药物作用 细胞 培养的 剂量效应关系 药物 内皮生长因子/拮抗剂和抑制剂 内皮生长因子/代谢 内皮 血管/药物作用 内皮 血管/代谢 淋巴因子/拮抗剂和抑制剂 淋巴因子/代谢 微循环/代谢 微循环/病理学 新生血管化 病理性/预防和控制 一氧化氮合酶/拮抗剂和抑制剂 一氧化氮合酶/代谢 大鼠 Sprague-Dawley 三唑类/药理学 血管内皮生长因子A 血管内皮生长因子类 动物 人类 男(雄)性 大鼠 

摘      要：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 Ca2+-mediated signal transduction, has been previously shown to inhibit angiogenesis in vitro and in vivo and to downregulate matrix metalloproteinase-2 in vitro. Diminished levels of intracellular Ca2+ 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 mu g/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 Ca2+-mediated signaling by CAI inhibits angiogenesis in vitro.