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      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.

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          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.

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          Author and article information

          Journal
          Mol. Carcinog.
          Molecular carcinogenesis
          1098-2744
          0899-1987
          Jan 29 2016
          Affiliations
          [1 ] Institut Pasteur de Tunis, LR11IPT04 Laboratoire d'Epidémiologie Moléculaire et de Pathologie Expérimentale Appliquée Aux Maladies Infectieuses, Tunis, Tunisia.
          [2 ] Université de Tunis El Manar, Tunis, Tunisia.
          [3 ] Department of Bioengineering, College of Engineering, Temple University, Philadelphia, Pennsylvania.
          [4 ] Institut Pasteur de Tunis, LR11IPT08 Laboratoire des Venins et Biomolécules thérapeutiques, Tunis, Tunisia.
          [5 ] Department of Biomedical, Centre Scientifique de Monaco, 8 Quai Antoine Ier, Monaco, Principality of Monaco.
          [6 ] Institut Pasteur de Tunis, LR11IPT02 Laboratoire de Recherche sur la Transmission, le Contrôle et l'Immunobiologie des Infections, Tunis, Tunisia.
          [7 ] Institute for Research on Cancer and Aging of Nice (IRCAN) UMR/7284 U1081, University of Nice Sophia Antipolis, Nice, France.
          Article
          10.1002/mc.22470
          26824338
          © 2016 Wiley Periodicals, Inc.

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