title: Selective killing of cancer cells by peptide-targeted delivery of an anti-microbial peptide.
abstract: Antimicrobial peptides selectively kill bacteria while maintaining low mammalian cell cytotoxicity. However, they become cytotoxic subsequent to internalization. Here we have conjugated the lytic peptide (KLAKLAK)(2) to either a cancer-cell binding peptide (LTVSPWY) selected from peptide libraries or to a gastrin-releasing peptide (GNHWAVGHLM) in order to direct the lytic peptide to cancer cells. Peptide cytotoxicity was tested in breast MCF-7 and MDA-MB-231 cancer cells. The fusion peptides were internalized by cancer cells, disintegrated the cell membrane and induced rapid killing of the cells with IC50 values as low as 4-7 μM. Peptide cytotoxicity was dependent on the targeting receptor. Indeed, addition of free targeting peptide reduced cell killing. Blood lymphocytes and normal human mammary epithelial cells were less sensitive to the fusion peptides. Although most of the cells were killed by necrosis, fusion peptides branched with DNA oligonucleotides induced apoptosis as assayed by annexin V staining and activation of caspase 3. Therefore, the new designed drug peptides might provide a potent and selective anticancer therapy.
authors.affiliation: Department of Immunology, Molecular Medicine Group, the Norwegian Radium Hospital, Institute for Cancer Research Montebello, N-0310, Oslo, Norway. mosioud@medisin.uio.no
authors.forename: Mouldy
authors.initials: M
authors.lastname: Sioud
authors.forename: Anne
authors.initials: A
authors.lastname: Mobergslien
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D005260:Female; D019886:Gastrin-Releasing Peptide / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D009841:Oligonucleotides / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding
chemical_list: D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D004337:Drug Carriers; D036341:Intercellular Signaling Peptides and Proteins; C535058:KLA peptide; D009841:Oligonucleotides; D009842:Oligopeptides; D010455:Peptides; C576676:leucyl-threonyl-valyl-seryl-prolyl-tryptophyl-tyrosine; D019886:Gastrin-Releasing Peptide