Morjen Maram, Honoré Stéphane, Bazaa Amine, Abdelkafi-Koubaa Zaineb, Ellafi Ameneallah, Mabrouk Kamel, Kovacic Hervé, El Ayeb Mohamed, Marrakchi Naziha, Luis José
Laboratoire des Venins et Biomolécules Thérapeutiques, Institut Pasteur de Tunis, Tunisia.
Aix Marseille Université, Institut National de la Santé et de la Recherche Médicale, UMR_S 911, Marseille, France; APHM, Hôpital Timone, Service Pharmacie, Marseille, France.
Microvasc Res. 2014 Sep;95:149-56. doi: 10.1016/j.mvr.2014.08.006. Epub 2014 Aug 28.
Development and homeostasis of the vascular system requires integrin-promoting endothelial cell adhesion, migration and survival. Nowadays, integrins represent potential targets for pharmacological agents and open new avenues for the control of metastatic spread in the treatment of tumor malignancies. We have already reported that PIVL, a serine protease inhibitor isolated from Macrovipera lebetina venom, displays an anti-tumor effect through interference with integrin receptor function. Here, we report that PIVL inhibits human vascular endothelial cell adhesion and migration onto fibrinogen and fibronectin in a dose-dependent manner without any cytotoxicity. Furthermore, we show that PIVL increases microtubule dynamic instability in HMEC-1 transfected with EGFP-tagged α-tubulin. Using Matrigel™ and chick chorioallantoic membrane assays, we demonstrate that PIVL exhibits a strong anti-angiogenic effect both in vitro and in vivo. Interestingly, results herein reveal that the potent anti-angiogenic properties of PIVL are mediated by its RGD-like motif ((41)RGN(43)).
血管系统的发育和稳态需要整合素促进内皮细胞的黏附、迁移和存活。如今，整合素是药物制剂的潜在靶点，并为控制肿瘤恶性肿瘤转移扩散开辟了新途径。我们已经报道，从黎凡特蝰蛇毒中分离出的丝氨酸蛋白酶抑制剂PIVL通过干扰整合素受体功能发挥抗肿瘤作用。在此，我们报道PIVL以剂量依赖的方式抑制人血管内皮细胞在纤维蛋白原和纤连蛋白上的黏附与迁移，且无任何细胞毒性。此外，我们发现PIVL增加了转染了EGFP标记的α-微管蛋白的HMEC-1中的微管动态不稳定性。使用基质胶™和鸡胚绒毛尿囊膜试验，我们证明PIVL在体外和体内均表现出强大的抗血管生成作用。有趣的是，本文结果表明PIVL强大的抗血管生成特性是由其类RGD基序（(41)RGN(43)）介导的。
