The oncolytic peptide LTX-315 induces cell death and DAMP release by mitochondria distortion in human melanoma cells

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 bovin...

Full description

Saved in:
Bibliographic Details
Published in:Oncotarget 2015-10, Vol.6 (33), p.34910-34923
Main Authors: Eike, Liv-Marie, Yang, Nannan, Rekdal, Øystein, Sveinbjørnsson, Baldur
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Basale medisinske, odontologiske og veterinærmedisinske fag: 710
Basic medical, dental and veterinary science disciplines: 710
Cell Death
Cell Line, Tumor
Cell Membrane - drug effects
Humans
Lactoferrin - pharmacology
Medical disciplines: 700
Medical molecular biology: 711
Medisinsk molekylærbiologi: 711
Medisinske Fag: 700
Melanoma - pathology
Membrane Potential, Mitochondrial - drug effects
Microscopy, Confocal
Microscopy, Electron, Transmission
Mitochondria - drug effects
Peptides - chemistry
Peptides - pharmacology
Research Paper
Structure-Activity Relationship
VDP
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.5308