title: Genotoxic and cytotoxic activity of host defense peptides against human soft tissue sarcoma in an in vitro model.
abstract: Soft tissue sarcomas (STSs) are a heterogeneous group of rare, mesenchymal tumors. Treatment with common chemotherapeutic drugs is consistently associated with low response rates and high rates of adverse toxic effects. Host defense peptides (HDPs) are used as part of innate immunity, and many of them act by directly lysing the target cell membrane. Studies have demonstrated high selectivity of HDP analogs against malignant cells because of a relative abundance of negative charges in malignant cell membranes, compared to normal cells. Our aim was to assess the toxic efficacy of [D]-K(6)L(9), [D]-K(3)H(3)L(9), and Protegrin-1 against the fibrosarcoma cell line, HT1080, and primary human fibroblasts to analyze the potential of these peptides as therapeutic options against STSs. Cell proliferation of the fibrosarcoma cell line, HT1080, and human fibroblasts was determined in vitro after treatment with [D]-K(6)L(9), [D]-K(3)H(3)L(9), and Protegrin-1. Genotoxicity was examined on the basis of the mild alkali version of single-cell gel electrophoresis (comet assay). Doxorubicin, a commonly used STS chemotherapeutic agent, served as the control. The native HDP, Protegrin-1, could show a cytotoxic tendency against malignant cells, but no selectivity in genotoxic trials. The synthetic peptide, [D]-K(6)L(9), could not show any selective oncolytic activity against sarcoma cells. [D]-K(3)H(3)L(9) has shown a tendency for toxic selectivity against malignant cells. There is a potential of developing suitable oncolytic candidates with selectivity against malignant cells. [D]-K(3)H(3)L(9) showed the first promising results, but there has to be further investigation to improve the therapeutic properties of HDPs.
authors.affiliation: Laboratory for Molecular Oncology and Wound Healing, Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany. lars.steinstraesser@ruhr-uni-bochum.de
authors.forename: Lars
authors.initials: L
authors.lastname: Steinstraesser
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hauk
authors.forename: Sammy
authors.initials: S
authors.lastname: Al-Benna
authors.forename: Stefan
authors.initials: S
authors.lastname: Langer
authors.forename: Andrej
authors.initials: A
authors.lastname: Ring
authors.forename: Marco
authors.initials: M
authors.lastname: Kesting
authors.forename: Holger
authors.initials: H
authors.lastname: Sudhoff
authors.forename: Mustafa
authors.initials: M
authors.lastname: Becerikli
authors.forename: Heiko
authors.initials: H
authors.lastname: Käfferlein
authors.forename: Frank
authors.initials: F
authors.lastname: Jacobsen
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020552:Comet Assay; D004317:Doxorubicin / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D009153:Mutagens / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*
chemical_list: D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D009153:Mutagens; D010455:Peptides; C094880:protegrin-1; D004317:Doxorubicin