title: Simplified, serine-rich theta-defensin analogues as antitumour peptides.
abstract: θ-defensins belong to the family of host defence peptides. They are the only known example of cyclic polypeptides in animal proteomes. This study presents the synthesis of simplified θ-defensin analogues with pairs of cysteine replaced either by alanine, leucine or serine residues. Cytotoxicity tests were performed on human mammary epithelial (HB2) and breast cancer (SKBR3, MDA-MB-231) cell lines to determine whether peptides are selectively targeting cancer cells. The effect of these peptides was also evaluated in 3D Matrigel cultures, which are based on extracellular matrix components and therefore closely represent in vivo conditions. Finally, to determine whether analogues are able to sensitize MDA-MB-231 triple-negative breast cancer cells to chemotherapeutics, we co-administrated peptides with cisplatin or doxorubicin hydrochloride also in 3D Matrigel cultures. Additionally, cytotoxicity towards peripheral blood mononuclear cells and haemolytic effect were examined for a chosen representative of synthesized compounds. The results showed that positively charged serine-containing θ-defensin derivatives were more cytotoxic towards breast cancer cells (SKBR3, MDA-MB-231) than towards mammary epithelial cells (HB2). Analogues enhanced the effect of cisplatin and doxorubicin hydrochloride on triple-negative breast cancer cell line (MDA-MB-231).
authors.affiliation: Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Gdansk, Poland.
authors.forename: Paulina
authors.identifier: 0000-0003-0226-6788
authors.initials: P
authors.lastname: Strzelecka
authors.affiliation: Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Czaplinska
authors.affiliation: Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, Poland.
authors.forename: Rafal
authors.initials: R
authors.lastname: Sadej
authors.affiliation: Department of Clinical Immunology and Transplantology, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wardowska
authors.affiliation: Department of Clinical Immunology and Transplantology, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Pikula
authors.affiliation: Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Gdansk, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Lesner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D023082:Defensins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012694:Serine / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D023082:Defensins; D010455:Peptides; C450142:theta-defensin; D012694:Serine; D004317:Doxorubicin; D002945:Cisplatin
keywords: antimicrobial peptides; breast cancer; host defence peptides; peptide-based drugs; theta-defensins