title: Lebein, a snake venom disintegrin, suppresses human colon cancer cells proliferation and tumor-induced angiogenesis through cell cycle arrest, apoptosis induction and inhibition of VEGF expression.
abstract: Lebein, is an heterodimeric disintegrin isolated from Macrovipera lebetina snake venom that was previously characterized as an inhibitor of ADP-induced platelet aggregation. In this study, we investigated the effect of Lebein on the p53-dependent growth of human colon adenocarcinoma cell lines. We found that Lebein significantly inhibited LS174 (p53wt), HCT116 (p53wt), and HT29 (p53mut) colon cancer cell viability by inducing cell cycle arrest through the modulation of expression levels of the tumor suppression factor p53, cell cycle regulating proteins cyclin D1, CDK2, CDK4, retinoblastoma (Rb), CDK1, and cyclin-dependent kinase inhibitors p21 and p27. Interestingly, Lebein-induced apoptosis of colon cancer cells was dependent on their p53 status. Thus, in LS174 cells, cell death was associated with PARP cleavage and the activation of caspases 3 and 8 while in HCT116 cells, Lebein induced caspase-independent apoptosis through increased expression of apoptosis inducing factor (AIF). In LS174 cells, Lebein triggers the activation of the MAPK ERK1/2 pathway through induction of reactive oxygen species (ROS). It also decreased cell adhesion and migration to fibronectin through down regulation of α5β1 integrin. Moreover, Lebein significantly reduced the expression of two angiogenesis stimulators, Vascular Endothelial Growth Factor (VEGF) and Neuropilin 1 (NRP1). It inhibited the VEGF-induced neovascularization process in the quail embryonic CAM system and blocked the development of human colon adenocarcinoma in nude mice. Overall, our work indicates that Lebein may be useful to design a new therapy against colon cancer. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Institut Pasteur de Tunis, LR11IPT04 Laboratoire d'Epidémiologie Moléculaire et de Pathologie Expérimentale Appliquée Aux Maladies Infectieuses, Tunis, Tunisia.|Université de Tunis El Manar, Tunis, Tunisia.
authors.forename: Ons
authors.initials: O
authors.lastname: Zakraoui
authors.affiliation: Department of Bioengineering, College of Engineering, Temple University, Philadelphia, Pennsylvania.
authors.forename: Cezary
authors.initials: C
authors.lastname: Marcinkiewicz
authors.affiliation: Institut Pasteur de Tunis, LR11IPT04 Laboratoire d'Epidémiologie Moléculaire et de Pathologie Expérimentale Appliquée Aux Maladies Infectieuses, Tunis, Tunisia.|Université de Tunis El Manar, Tunis, Tunisia.
authors.forename: Zohra
authors.initials: Z
authors.lastname: Aloui
authors.affiliation: Université de Tunis El Manar, Tunis, Tunisia.|Institut Pasteur de Tunis, LR11IPT08 Laboratoire des Venins et Biomolécules thérapeutiques, Tunis, Tunisia.
authors.forename: Houcemeddine
authors.initials: H
authors.lastname: Othman
authors.affiliation: Department of Biomedical, Centre Scientifique de Monaco, 8 Quai Antoine Ier, Monaco, Principality of Monaco.
authors.forename: Renaud
authors.initials: R
authors.lastname: Grépin
authors.affiliation: Université de Tunis El Manar, Tunis, Tunisia.|Institut Pasteur de Tunis, LR11IPT02 Laboratoire de Recherche sur la Transmission, le Contrôle et l'Immunobiologie des Infections, Tunis, Tunisia.
authors.forename: Meriam
authors.initials: M
authors.lastname: Haoues
authors.affiliation: Université de Tunis El Manar, Tunis, Tunisia.|Institut Pasteur de Tunis, LR11IPT02 Laboratoire de Recherche sur la Transmission, le Contrôle et l'Immunobiologie des Infections, Tunis, Tunisia.
authors.forename: Makram
authors.initials: M
authors.lastname: Essafi
authors.affiliation: Université de Tunis El Manar, Tunis, Tunisia.|Institut Pasteur de Tunis, LR11IPT08 Laboratoire des Venins et Biomolécules thérapeutiques, Tunis, Tunisia.
authors.forename: Najet
authors.initials: N
authors.lastname: Srairi-Abid
authors.forename: Ammar
authors.initials: A
authors.lastname: Gasmi
authors.affiliation: Institut Pasteur de Tunis, LR11IPT04 Laboratoire d'Epidémiologie Moléculaire et de Pathologie Expérimentale Appliquée Aux Maladies Infectieuses, Tunis, Tunisia.|Université de Tunis El Manar, Tunis, Tunisia.
authors.forename: Habib
authors.initials: H
authors.lastname: Karoui
authors.affiliation: Institute for Research on Cancer and Aging of Nice (IRCAN) UMR/7284 U1081, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Pagès
authors.affiliation: Institut Pasteur de Tunis, LR11IPT04 Laboratoire d'Epidémiologie Moléculaire et de Pathologie Expérimentale Appliquée Aux Maladies Infectieuses, Tunis, Tunisia.|Université de Tunis El Manar, Tunis, Tunisia.
authors.forename: Khadija
authors.initials: K
authors.lastname: Essafi-Benkhadir
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002645:Chickens; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008819:Mice, Nude; D008958:Models, Molecular; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D014757:Viper Venoms / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D019012:Integrin beta1; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D014757:Viper Venoms; C428664:lebein
keywords: Lebein; cellular effectors; colon cancer; disintegrin; tumor growth