Oncolytic designer host defense peptide suppresses growth of human liposarcoma.
Sarcomas display a rare and heterogeneous group of tumors. Treatment options are limited. Host defense peptides (HDPs), effector molecules of the innate immune system, might provide a more effective treatment option. The aim of our study was to analyze the oncolytic activity and mode of action of a designer HDP. In vitro, the human liposarcoma cell line SW-872 and primary human fibroblasts as a control were exposed to [D]-K(3)H(3)L(9), a 15-mer D,L-amino acid designer peptide. Cell growth (MTT assay), proliferation (BrdU assay) and genotoxicity (TUNEL assay) were analyzed. The mode of action was examined via fluorescence-activated cell sorter (FACS) analysis and confocal laser scanning microscopy. In vivo, [D]-K(3)H(3)L(9) (n = 7) was administered intratumorally in a SW-872 xenograft mouse model (Foxn1nu/nu). Phosphate buffered saline served as a control (n = 5). After 4 weeks, tumor sections were histologically analyzed with respect to proliferation, cytotoxicity, vessel density and signs of apoptosis and necrosis, respectively. In vitro, [D]-K(3)H(3)L(9) highly significantly (p < 0.01) inhibited cell metabolism and proliferation. TUNEL assay revealed corresponding genotoxicity. FACS analysis suggested induction of necrosis as a cause of cell death. The mean tumor volume of the control group exponentially increased sevenfold, whereas the mean tumor growth was negligible in the treatment group. Macroscopically, [D]-K(3)H(3)L(9) induced full tumor remission in 43% of treated animals and partial remission in 43%. Vessel density was significantly reduced by 52%. Morphological analyses supported the hypothesis of cancer cell killing by necrosis. In summary, [D]-K(3)H(3)L(9) exerts very promising oncolytic activity on liposarcoma cells. Our study demonstrates the potential of HDPs as a novel therapeutic option in future soft tissue sarcoma therapy.
Steinstraesser
Lars
L
Department of Plastic and Reconstructive Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Nordrhein-Westfalen, Germany. lars.steinstraesser@ruhr-uni-bochum.de
Schubert
Cornelius
C
Hauk
Jennifer
J
Becerikli
Mustafa
M
Stricker
Ingo
I
Koeller
Manfred
M
Hatt
Hanns
H
von Duering
Monika
M
Shai
Yechiel
Y
Steinau
Hans-Ulrich
HU
Jacobsen
Frank
F
D000818:Animals; D002455:Cell Division; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D008080:Liposarcoma / Q000473:pathology*; D051379:Mice; D018613:Microscopy, Confocal; D050130:Oncolytic Virotherapy; D010455:Peptides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D010455:Peptides