Abstract
Malignant melanoma is the most aggressive and deadliest form of skin cancer due to its highly metastatic potential, which calls for new and improved therapies. Cationic antimicrobial peptides (CAPs) are naturally occurring molecules found in most species, in which they play a significant role in the first line of defense against pathogens, and several CAPs have shown promising potential as novel anticancer agents. Structure–activity relationship studies on the CAP bovine lactoferricin allowed us to de novo design short chemically modified lytic anticancer peptides. In the present study, we investigated the in vivo antitumor effects of LTX-315 against intradermally established B16 melanomas in syngeneic mice. Intratumoral administration of LTX-315 resulted in tumor necrosis and the infiltration of immune cells into the tumor parenchyma followed by complete regression of the tumor in the majority of the animals. LTX-315 induced the release of danger-associated molecular pattern molecules such as the high mobility group box-1 protein in vitro and the subsequent upregulation of proinflammatory cytokines such as interleukin (IL) 1β, IL6 and IL18 in vivo. Animals cured by LTX-315 treatment were protected against a re-challenge with live B16 tumor cells both intradermally and intravenously. Together, our data indicate that intratumoral treatment with LTX-315 can provide local tumor control followed by protective immune responses and has potential as a new immunotherapeutic agent.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-014-1540-0) contains supplementary material, which is available to authorized users.
Highlights
Malignant melanoma, which develops from a neoplastic transformation of melanocytes, is the most aggressive formCancer Immunol Immunother (2014) 63:601–613 of skin cancer, and the number of incidents has increased annually by 2.8 % since 1981 in the US alone [1]
Previous studies have shown that naturally occurring Cationic antimicrobial peptides (CAPs) such as the cell-penetrating peptide, crotamine, display potent cytotoxic activity against B16 melanoma cells in vitro as well as B16 melanomas established in syngeneic mice [38]
In accordance with studies on other CAPs, the specificity of LTX-315 for tumor cells is probably due to differences in cell membrane composition between cancer cells and non-malignant cells
Summary
Cancer Immunol Immunother (2014) 63:601–613 of skin cancer, and the number of incidents has increased annually by 2.8 % since 1981 in the US alone [1]. With the increase in the number of patients, the need for new and improved therapies is prevalent. Chemotherapy, immunotherapy and radiation therapy [2, 3], while the prognosis and treatment given depends on at which stage the melanoma is diagnosed (Stage I, II, III or IV). Improvements in treatment regimens have primarily been within immunotherapy, as demonstrated by the approval of Ipilimumab (YervoyTM; Bristol-Myers Squibb, USA) in 2011. Together with ongoing research on targeted therapy, there is an increasing focus on the development of new immunotherapeutic drugs [5, 6]
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