In vitro antiangiogenic activity of selective somatostatin subtype-1 receptor agonists
In vitro antiangiogenic activity of selective somatostatin subtype-1 receptor agonists
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DOI：
10.1111/j.1365-2362.2007.01848.x
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发表时间：
2007-09-01
影响因子：
5.5
通讯作者：
Del Tacca, M.
中科院分区：
文献类型：
--
作者：
Bocci, G.;Culler, M. D.;Del Tacca, M.
背景人血管内皮细胞（动脉和静脉）显示高水平的生长抑素1型受体（sst（1））。本研究的目的是研究新型生长抑素类似物的抑制作用，对人sst（1）具有高度选择性，对体外血管生成及其对血管内皮生长因子（VEGF）和血管内皮生长因子受体-2（VEGFR-2）表达的调节的影响。23926检测其阻止人内皮HMEC-1细胞增殖和迁移的能力，结果生长抑素sst（1）受体-选择性激动剂BIM-23745和BIM-23926显示出对内皮细胞增殖的抑制作用（例如，10（-6）M BIM-23475，40.0 +/- 2.1% vs. 100%对照; 10（-7）M BIM-23926，55.3 +/- 3.3% vs. 100%对照品），迁移（例如，10（-7）M BIM-23475，35.0 +/- 1.56% vs. 100%对照; 10（-7）M BIM-23926，53.7 +/- 1.77% vs. 100%对照）和微血管发芽（例如10（-8）M BIM-23475，42.8 +/- 5.6% vs 100%对照; 10（-7）M BIM-23926，17.2 +/- 11.8% vs 100%对照）。暴露于BIM-23745和BIM-23926 24小时和72小时的细胞的小但显著百分比呈现典型的凋亡形态。此外，这两种类似物均显着抑制在纤维蛋白基质中生长144小时的内皮细胞中的VEGF和VEGFR-2基因表达以及条件培养基中的VEGF分泌。结论对内皮细胞活性的抑制表明，生长激素抑制素sst（1）受体选择性激动剂在涉及血管生成的增殖性疾病中具有潜在的治疗用途。
Background Endothelial cells of human blood vessels (arteries and veins) show high levels of somatostatin subtype-1 receptor (sst(1)). The aim of the present study is to investigate the inhibitory effects of novel somatostatin analogs, highly selective for human sst(1), on in vitro angiogenesis and their modulation of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) expression.Materials and methods Somatostatin analogs BIM-23745 and BIM-23926 were tested for their ability to prevent proliferation and migration of human endothelial HMEC-1 cells, to modulate VEGF and VEGFR-2 expression and to inhibit sprouting of microvessels from cultured human placental vessel explants in fibrin matrix for 28 days.Results The somatostatin sst(1) receptor-selective agonists, BIM-23745 and BIM-23926 showed a suppression of endothelial proliferation (e.g. 10(-6) M BIM-23475, 40.0 +/- 2.1% vs. 100% of controls; 10(-7) M BIM-23926, 55.3 +/- 3.3% vs. 100% of controls), migration (e.g. 10(-7) M BIM-23475, 35.0 +/- 1.56% vs. 100% of controls; 10(-7) M BIM-23926, 53.7 +/- 1.77% vs. 100% of controls) and microvessel sprouting (e.g. 10(-8) M BIM-23475, 42.8 +/- 5.6% vs. 100% of controls; 10(-7) M BIM-23926, 17.2 +/- 11.8% vs. 100% of controls). A small but significant percentage of cells exposed to BIM-23745 and BIM-23926 for 24 h and for 72 h presented typical apoptotic morphology. Moreover, both the analogs significantly inhibit VEGF and VEGFR-2 gene expression in endothelial cells grown for 144 h in a fibrin matrix and the VEGF secretion in conditioned media.Conclusions The inhibition of endothelial activities suggests potential therapeutic utility for administration of somatostatin sst(1) receptor-selective agonists in the proliferative diseases involving angiogenesis.