title: The oncolytic peptide LTX-315 induces cell death and DAMP release by mitochondria distortion in human melanoma cells.
abstract: Host defense peptides (HDPs) are naturally occurring molecules found in most species, in which they play a significant role in the first line defense against intruding pathogens, and several HDPs have been shown to possess anticancer activity. Structure-activity relationship studies on the HDP bovine lactoferricin revealed a de novo design of a nonamer peptide LTX-315, with oncolytic properties. In the present study, we investigated the oncolytic activity of LTX-315 in human melanoma cells (A375). LTX-315 induced a rapid plasma membrane disruption and cell death within 2 hours. At a low concentration, fluorescence-labeled LTX-315 was internalized and accumulated in cytoplasmic vacuoles in close proximity to the mitochondria. The mitochondrial membrane potential was shown to depolarize as a consequence of LTX-315 treatment and at ultrastructural level, the mitochondria morphology was significantly altered. Release of danger signals (DAMPs) such as ATP, Cytochrome C and HMGB1 into the cell supernatant of cultured cells was evident minutes after peptide treatment. The oncolytic effect of LTX-315 involving perturbation of both the cell membrane and the mitochondria with subsequent release of DAMPs may highlight the ability of LTX-315 to induce complete regression and long-term protective immune responses as previously reported in experimental animal models.
authors.affiliation: Department of Molecular Inflammation Research and Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
authors.forename: Liv-Marie
authors.initials: LM
authors.lastname: Eike
authors.affiliation: Department of Community Medicine, Faculty of Health University of Tromsø, Tromsø, Norway.
authors.forename: Nannan
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Molecular Inflammation Research and Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.|Lytix Biopharma, Oslo, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Rekdal
authors.affiliation: Department of Molecular Inflammation Research and Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
authors.forename: Baldur
authors.initials: B
authors.lastname: Sveinbjørnsson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects; D006801:Humans; D007781:Lactoferrin / Q000494:pharmacology*; D008545:Melanoma / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; C082171:lactoferricin B; D007781:Lactoferrin
keywords: DAMPs; melanoma; oncolytic peptide