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Journal Reference
Oncotarget. 2015;6(33):34910-23.
Eike LM1, Yang N2, Rekdal Ø1,3, Sveinbjørnsson B1.
[expand title=”Show Affiliations”]- Department of Molecular Inflammation Research and Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
- Department of Community Medicine, Faculty of Health University of Tromsø, Tromsø, Norway.
- Lytix Biopharma, Oslo, Norway.
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.
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