title: Lebein, a Snake Venom Disintegrin, Induces Apoptosis in Human Melanoma Cells.
abstract: Melanoma, the most threatening form of skin cancer, has a very poor prognosis and is characterized by its very invasive and chemoresistant properties. Despite the recent promising news from the field of immunotherapy, there is an urgent need for new therapeutic approaches that are free of resistance mechanisms and side effects. Anti-neoplasic properties have been highlighted for different disintegrins from snake venom including Lebein; however, the exact effect of Lebein on melanoma has not yet been defined. In this study, we showed that Lebein blocks melanoma cell proliferation and induces a more differentiated phenotype with inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and microphthalmia-associated transcription factor (MITF) overexpression. Melanoma cells became detached but were less invasive with upregulation of E-cadherin after Lebein exposure. Lebein induced a caspase-independent apoptotic program with apoptosis inducing factor (AIF), BCL-2-associated X protein (BAX) and Bim overexpression together with downregulation of B-cell lymphoma-2 (BCL-2). It generated a distinct response in reactive oxygen species (ROS) generation and p53 levels depending on the p53 cell line status (wild type or mutant). Therefore, we propose Lebein as a new candidate for development of potential therapies for melanoma.
authors.affiliation: Laboratoire d'Epid&#233;miologie Mol&#233;culaire et Pathologie Exp&#233;rimentale Appliqu&#233;e Aux Maladies Infectieuses (LR11IPT04), Institut Pasteur de Tunis, 1002 Tunis, Tunisia. ma_nel85@hotmail.com.|Universit&#233; de Tunis El Manar, 1068 Tunis, Tunisia. ma_nel85@hotmail.com.|Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, 30100 Espinardo, Murcia, Spain. ma_nel85@hotmail.com.
authors.forename: Manel B
authors.initials: MB
authors.lastname: Hammouda
authors.affiliation: Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, 30100 Espinardo, Murcia, Spain. fermontenegro@um.es.
authors.forename: María F
authors.initials: MF
authors.lastname: Montenegro
authors.affiliation: Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, 30100 Espinardo, Murcia, Spain. sancampo@um.es.
authors.forename: Luis
authors.initials: L
authors.lastname: Sánchez-Del-Campo
authors.affiliation: Laboratoire d'Epid&#233;miologie Mol&#233;culaire et Pathologie Exp&#233;rimentale Appliqu&#233;e Aux Maladies Infectieuses (LR11IPT04), Institut Pasteur de Tunis, 1002 Tunis, Tunisia. zakraoui-ons@hotmail.fr.|Universit&#233; de Tunis El Manar, 1068 Tunis, Tunisia. zakraoui-ons@hotmail.fr.
authors.forename: Ons
authors.initials: O
authors.lastname: Zakraoui
authors.affiliation: Laboratoire d'Epid&#233;miologie Mol&#233;culaire et Pathologie Exp&#233;rimentale Appliqu&#233;e Aux Maladies Infectieuses (LR11IPT04), Institut Pasteur de Tunis, 1002 Tunis, Tunisia. zohra.aloui@pasteur.rns.tn.|Universit&#233; de Tunis El Manar, 1068 Tunis, Tunisia. zohra.aloui@pasteur.rns.tn.
authors.forename: Zohra
authors.initials: Z
authors.lastname: Aloui
authors.affiliation: Laboratoire d'Epid&#233;miologie Mol&#233;culaire et Pathologie Exp&#233;rimentale Appliqu&#233;e Aux Maladies Infectieuses (LR11IPT04), Institut Pasteur de Tunis, 1002 Tunis, Tunisia. ichrakriahi@live.com.|Universit&#233; de Tunis El Manar, 1068 Tunis, Tunisia. ichrakriahi@live.com.
authors.forename: Ichrak
authors.initials: I
authors.lastname: Riahi-Chebbi
authors.affiliation: Laboratoire d'Epid&#233;miologie Mol&#233;culaire et Pathologie Exp&#233;rimentale Appliqu&#233;e Aux Maladies Infectieuses (LR11IPT04), Institut Pasteur de Tunis, 1002 Tunis, Tunisia. habib.karoui@pasteur.rns.tn.|Universit&#233; de Tunis El Manar, 1068 Tunis, Tunisia. habib.karoui@pasteur.rns.tn.
authors.forename: Habib
authors.initials: H
authors.lastname: Karoui
authors.affiliation: Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, 30100 Espinardo, Murcia, Spain. neptuno@um.es.|Instituto Murciano de Investigaci&#243;n Biosanitaria (IMIB), 30120 Murcia, Spain. neptuno@um.es.
authors.forename: José Neptuno
authors.initials: JN
authors.lastname: Rodríguez-López
authors.affiliation: Laboratoire d'Epid&#233;miologie Mol&#233;culaire et Pathologie Exp&#233;rimentale Appliqu&#233;e Aux Maladies Infectieuses (LR11IPT04), Institut Pasteur de Tunis, 1002 Tunis, Tunisia. essafi.khadija@pasteur.rns.tn.|Universit&#233; de Tunis El Manar, 1068 Tunis, Tunisia. essafi.khadija@pasteur.rns.tn.
authors.forename: Khadija
authors.initials: K
authors.lastname: Essafi-Benkhadir
mesh_terms: D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014757:Viper Venoms / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C513384:CDH1 protein, human; D015820:Cadherins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D014757:Viper Venoms; C428664:lebein; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Lebein; Macrovipera lebetina; apoptosis; disintegrin; melanoma; snake venom