title: PIVL, a snake venom Kunitz-type serine protease inhibitor, inhibits in vitro and in vivo angiogenesis.
abstract: 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)).
authors.affiliation: Laboratoire des Venins et Biomolécules Thérapeutiques, Institut Pasteur de Tunis, Tunisia. Electronic address: maram.morjen@yahoo.fr.
authors.forename: Maram
authors.initials: M
authors.lastname: Morjen
authors.affiliation: 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.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Honoré
authors.affiliation: Laboratoire des Venins et Biomolécules Thérapeutiques, Institut Pasteur de Tunis, Tunisia.
authors.forename: Amine
authors.initials: A
authors.lastname: Bazaa
authors.affiliation: Laboratoire des Venins et Biomolécules Thérapeutiques, Institut Pasteur de Tunis, Tunisia.
authors.forename: Zaineb
authors.initials: Z
authors.lastname: Abdelkafi-Koubaa
authors.affiliation: Laboratoire des Venins et Biomolécules Thérapeutiques, Institut Pasteur de Tunis, Tunisia.
authors.forename: Ameneallah
authors.initials: A
authors.lastname: Ellafi
authors.affiliation: Equipe CROPS, Institut de Chimie Radicalaire - UMR 7273, Université d'Aix-Marseille, Site de Saint Jérôme, Av. Escadrille Normandie Niemen, 13397 Marseille, France.
authors.forename: Kamel
authors.initials: K
authors.lastname: Mabrouk
authors.affiliation: APHM, Hôpital Timone, Service Pharmacie, Marseille, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Kovacic
authors.affiliation: Laboratoire des Venins et Biomolécules Thérapeutiques, Institut Pasteur de Tunis, Tunisia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Ayeb
authors.affiliation: Laboratoire des Venins et Biomolécules Thérapeutiques, Institut Pasteur de Tunis, Tunisia; Faculté de Médecine de Tunis, Tunisia.
authors.forename: Naziha
authors.initials: N
authors.lastname: Marrakchi
authors.affiliation: APHM, Hôpital Timone, Service Pharmacie, Marseille, France.
authors.forename: José
authors.initials: J
authors.lastname: Luis
mesh_terms: D020816:Amino Acid Motifs; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D014757:Viper Venoms / Q000737:chemistry*
chemical_list: D020533:Angiogenesis Inhibitors; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; C000598507:PIVL, Macrovipera lebetina; D015842:Serine Proteinase Inhibitors; D014757:Viper Venoms
keywords: Angiogenesis; Chorioallantoic membrane assay; Integrin; Microtubule dynamics; Migration