The oncolytic peptide LTX-315 induces cell death and DAMP release by mitochondria distortion in human melanoma cells
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Liv-Marie Eike1, Nannan Yang2, Øystein Rekdal1,3, Baldur Sveinbjørnsson1
1Department of Molecular Inflammation Research, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
2Department of Community Medicine, Faculty of Health University of Tromsø, Tromsø, Norway
3Lytix Biopharma, Oslo, Norway
Baldur Sveinbjørnsson, e-mail: [email protected]
Keywords: oncolytic peptide, DAMPs, melanoma
Received: March 25, 2015 Accepted: October 01, 2015 Published: October 13, 2015
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.
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