title: A proapoptotic peptide conjugated to penetratin selectively inhibits tumor cell growth.
abstract: The peptide KLA (acetyl-(KLAKLAK)2-NH2), which is rather non toxic for eukaryotic cell lines, becomes active when coupled to the cell penetrating peptide, penetratin (Pen), by a disulfide bridge. Remarkably, the conjugate KLA-Pen is cytotoxic, at low micromolar concentrations, against a panel of seven human tumor cell lines of various tissue origins, including cells resistant to conventional chemotherapy agents but not to normal human cell lines. Live microscopy on cells possessing fluorescent labeled mitochondria shows that in tumor cells, KLA-Pen had a strong impact on mitochondria tubular organization instantly resulting in their aggregation, while the unconjugated KLA and pen peptides had no effect. But, mitochondria in various normal cells were not affected by KLA-Pen. The interaction with membrane models of KLA-Pen, KLA and penetratin were studied using dynamic light scattering, calorimetry, plasmon resonance, circular dichroism and ATR-FTIR to unveil the mode of action of the conjugate. To understand the selectivity of the conjugate towards tumor cell lines and its action on mitochondria, lipid model systems composed of zwitterionic lipids were used as mimics of normal cell membranes and anionic lipids as mimics of tumor cell and mitochondria membrane. A very distinct mode of interaction with the two model systems was observed. KLA-Pen may exert its deleterious and selective action on cancer cells by the formation of pores with an oblique membrane orientation and establishment of important hydrophobic interactions. These results suggest that KLA-Pen could be a lead compound for the design of cancer therapeutics.
authors.affiliation: Chimie et Biologie des Membranes et Nanoobjets, CBMN CNRS UMR 5248, Université Bordeaux 1, Allée Geoffroy de Saint Hilaire, 33600 Pessac, France.
authors.forename: Isabel D
authors.initials: ID
authors.lastname: Alves
authors.affiliation: Aix-Marseille Université, INSERM, CRO2 UMR S 911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, 27, Boulevard Jean Moulin, 13005 Marseille, France.
authors.forename: Manon
authors.initials: M
authors.lastname: Carré
authors.affiliation: Aix-Marseille Université, INSERM, CRO2 UMR S 911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, 27, Boulevard Jean Moulin, 13005 Marseille, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Montero
authors.affiliation: Chimie et Biologie des Membranes et Nanoobjets, CBMN CNRS UMR 5248, Université Bordeaux 1, Allée Geoffroy de Saint Hilaire, 33600 Pessac, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Castano
authors.affiliation: Chimie et Biologie des Membranes et Nanoobjets, CBMN CNRS UMR 5248, Université Bordeaux 1, Allée Geoffroy de Saint Hilaire, 33600 Pessac, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lecomte
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 6, Laboratoire des BioMolécules, 4 place Jussieu, CNRS UMR 7203 and ENS, LBM, Dpt de Chimie, 24, Rue Lhomond, 75005 Paris.
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Marquant
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 6, Laboratoire des BioMolécules, 4 place Jussieu, CNRS UMR 7203 and ENS, LBM, Dpt de Chimie, 24, Rue Lhomond, 75005 Paris.
authors.forename: Pascaline
authors.initials: P
authors.lastname: Lecorché
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 6, Laboratoire des BioMolécules, 4 place Jussieu, CNRS UMR 7203 and ENS, LBM, Dpt de Chimie, 24, Rue Lhomond, 75005 Paris.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burlina
authors.affiliation: Laboratoire de Chimie des Polymères Organiques, LCPO CNRS UMR 5629, 16 avenue Pey-Berland, 33600 Pessac, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Schatz
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 6, Laboratoire des BioMolécules, 4 place Jussieu, CNRS UMR 7203 and ENS, LBM, Dpt de Chimie, 24, Rue Lhomond, 75005 Paris.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Sagan
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 6, Laboratoire des BioMolécules, 4 place Jussieu, CNRS UMR 7203 and ENS, LBM, Dpt de Chimie, 24, Rue Lhomond, 75005 Paris.
authors.forename: Gérard
authors.initials: G
authors.lastname: Chassaing
authors.affiliation: Aix-Marseille Université, INSERM, CRO2 UMR S 911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, 27, Boulevard Jean Moulin, 13005 Marseille, France; APHM, Hôpital Timone, 13005 Marseille.
authors.forename: Diane
authors.initials: D
authors.lastname: Braguer
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 6, Laboratoire des BioMolécules, 4 place Jussieu, CNRS UMR 7203 and ENS, LBM, Dpt de Chimie, 24, Rue Lhomond, 75005 Paris. Electronic address: solange.lavielle@upmc.fr.
authors.forename: Solange
authors.initials: S
authors.lastname: Lavielle
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D002152:Calorimetry, Differential Scanning; D002352:Carrier Proteins / Q000494:pharmacology*; D057846:Cell-Penetrating Peptides; D002942:Circular Dichroism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008081:Liposomes; D008563:Membrane Lipids / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects*; D051336:Mitochondrial Membranes / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D017550:Spectroscopy, Fourier Transform Infrared; D014407:Tumor Cells, Cultured
chemical_list: D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D036341:Intercellular Signaling Peptides and Proteins; C535058:KLA peptide; D008081:Liposomes; D008563:Membrane Lipids; D010455:Peptides; C414409:penetratin
keywords: Apoptotic peptide; Cell penetrating peptide; Lipid model systems; Mitochondria disruption; Peptide lipid interaction; Tumor cell growth inhibition