The Cytolytic Amphipathic β(2,2)-Amino Acid LTX-401 Induces DAMP Release in Melanoma Cells and Causes Complete Regression of B16 Melanoma

Liv-Marie Eike; Brynjar Mauseth; Ketil André Camilio; Øystein Rekdal; Baldur Sveinbjørnsson

doi:10.1371/journal.pone.0148980

The Cytolytic Amphipathic β(2,2)-Amino Acid LTX-401 Induces DAMP Release in Melanoma Cells and Causes Complete Regression of B16 Melanoma

PLoS One. 2016 Feb 16;11(2):e0148980. doi: 10.1371/journal.pone.0148980. eCollection 2016.

Authors

Liv-Marie Eike¹, Brynjar Mauseth¹, Ketil André Camilio¹, Øystein Rekdal^{1

2}, Baldur Sveinbjørnsson^{1

3}

Affiliations

¹ Department of Molecular Inflammation Research, Institute of Medical Biology, Faculty of Health, University of Tromsø, N-9037, Tromsø, Norway.
² Lytix Biopharma, Gaustad Alléen, Oslo, Norway.
³ Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.

Abstract

In the present study we examined the ability of the amino acid derivative LTX-401 to induce cell death in cancer cell lines, as well as the capacity to induce regression in a murine melanoma model. Mode of action studies in vitro revealed lytic cell death and release of danger-associated molecular pattern molecules, preceded by massive cytoplasmic vacuolization and compromised lysosomes in treated cells. The use of a murine melanoma model demonstrated that the majority of animals treated with intratumoural injections of LTX-401 showed complete and long-lasting remission. Taken together, these results demonstrate the potential of LTX-401 as an immunotherapeutic agent for the treatment of solid tumors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Animals
Antimicrobial Cationic Peptides / chemical synthesis
Antimicrobial Cationic Peptides / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Survival / drug effects
Cytochromes c / metabolism
Cytotoxins / chemical synthesis
Cytotoxins / pharmacology*
Erythrocytes / drug effects
Female
HMGB1 Protein / metabolism
Hemolysis / drug effects
Humans
Inhibitory Concentration 50
Injections, Intralesional
Lysosomes / drug effects
Lysosomes / metabolism
Lysosomes / ultrastructure
Melanoma, Experimental / drug therapy*
Melanoma, Experimental / metabolism
Melanoma, Experimental / ultrastructure
Mice
Mice, Inbred C57BL
Rats
Remission Induction
Skin Neoplasms / drug therapy*
Skin Neoplasms / metabolism
Skin Neoplasms / ultrastructure
Vacuoles / drug effects
Vacuoles / metabolism
Vacuoles / ultrastructure
beta-Alanine / analogs & derivatives*
beta-Alanine / chemical synthesis
beta-Alanine / pharmacology

Substances

Antimicrobial Cationic Peptides
Antineoplastic Agents
Cytotoxins
HMGB1 Protein
HMGB1 protein, mouse
LTX-401
beta-Alanine
Adenosine Triphosphate
Cytochromes c

Grants and funding

The study was funded by grants from the University of Tromsø, Lytix Biopharma and the Northern Regional Health Authority and the University Hospital of North Norway. Lytix Biopharma AS provided support in the form of salaries for the authors [B.S, Ø.R and K.A.C], but did not have any additional role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.