Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Eur J Pharmacol. 2010 Mar 25;630(1-3):53-60. doi: 10.1016/j.ejphar.2009.12.036. Epub 2010 Jan 11.
Angiogenesis is observed in many diseases, such as tumor progression, diabetes and rheumatoid arthritis; it is a process that involves proliferation, migration, differentiation and tube formation of endothelial cells. Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis by induction of these endothelial functions. Thus, inhibition of these critical angiogenic steps is a practical therapeutic strategy for those diseases. NP-184 is a substituted benzimidazole analogue which exhibits a potent anti-thrombotic activity. In this report, NP-184 inhibited the viability of human umbilical vascular endothelial cells (HUVEC) in a concentration-dependent manner, and caused cell apoptosis as examined by cell-cycle analysis and Annexin V staining with flow cytometry. NP-184 also concentration-dependently inhibited the HUVEC migration, tube formation on Matrigel, and rat aortic ring sprouting stimulated by VEGF. Regarding the intracellular signal transduction, NP-184 concentration-dependently interfered with the activation of AKT, ERK and the nuclear translocation of NF-kappaB. In vivo study showed that NP-184 dose-dependently reduced angiogenesis in Matrigel plug assay. These results indicate that NP-184 is a potential candidate for developing the treatment of angiogenesis related-diseases.
血管生成发生于许多疾病中，如肿瘤进展、糖尿病和类风湿性关节炎；它是一个涉及内皮细胞增殖、迁移、分化和管腔形成的过程。血管内皮生长因子（VEGF）通过诱导这些内皮功能在血管生成中发挥重要作用。因此，抑制这些关键的血管生成步骤是治疗这些疾病的一种实用的治疗策略。NP-184 是一种取代的苯并咪唑类似物，具有很强的抗血栓活性。在本报告中，NP-184 以浓度依赖性方式抑制人脐静脉内皮细胞（HUVEC）的活力，并通过细胞周期分析和流式细胞术检测 Annexin V 染色观察到细胞凋亡。NP-184 还浓度依赖性地抑制 HUVEC 迁移、Matrigel 上的管腔形成以及 VEGF 刺激的大鼠主动脉环发芽。关于细胞内信号转导，NP-184 浓度依赖性地干扰 AKT、ERK 的激活和 NF-κB 的核易位。体内研究表明，NP-184 剂量依赖性地减少 Matrigel 塞中血管生成。这些结果表明 NP-184 是开发治疗与血管生成相关疾病的潜在候选药物。
