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

// Liv-Marie Eike 1 , Nannan Yang 2 , Øystein Rekdal 1, 3 , Baldur Sveinbjørnsson 1 1 Department of Molecular Inflammation Research, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway 2 Department of Community Medicine, Faculty of Health University of Tromsø, Tromsø, Norway 3 Lytix Biopharma, Oslo, Norway Correspondence to: Baldur Sveinbjørnsson, e-mail: baldur.sveinbjornsson@uit.no Keywords: oncolytic peptide, DAMPs, melanoma Received: March 25, 2015      Accepted: October 01, 2015      Published: October 13, 2015 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.