title: Cyclotides: a novel type of cytotoxic agents.
abstract: Cytotoxic activities of three naturally occurring macrocyclic peptides (cyclotides) isolated from the two violets, Viola arvensis Murr. and Viola odorata L., were investigated. A nonclonogenic fluorometric microculture assay was used to examine cytotoxicity in a panel of 10 human tumor cell lines representing defined types of cytotoxic drug resistance. Additionally, primary cultures of tumor cells from patients, and for comparison normal lymphocytes, were used to quantify cytotoxic activity. All three cyclotides, varv A, varv F, and cycloviolacin 02, exhibited strong cytotoxic activities, which varied in a dose-dependent manner. Cycloviolacin 02 was the most potent in all cell lines (IC50 0.1-0.3 microM), followed by varv A (IC50 2.7-6.35 microM) and varv F (IC50 2.6-7.4 microM), respectively. Activity profiles of the cyclotides differed significantly from those of antitumor drugs in clinical use, which may indicate a new mode of action. This, together with the exceptional chemical and biological stability of cyclotides, makes them interesting in particular for their potential as pharmacological tools and possibly as leads to antitumor agents.
authors.affiliation: Division of Pharmacognosy, Department of Medicinal Chemistry, BMC, Uppsala University, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Lindholm
authors.forename: Ulf
authors.initials: U
authors.lastname: Göransson
authors.forename: Senia
authors.initials: S
authors.lastname: Johansson
authors.forename: Per
authors.initials: P
authors.lastname: Claeson
authors.forename: Joachim
authors.initials: J
authors.lastname: Gullbo
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.forename: Lars
authors.initials: L
authors.lastname: Bohlin
authors.forename: Anders
authors.initials: A
authors.lastname: Backlund
mesh_terms: D000595:Amino Acid Sequence; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D047169:Cyclotides; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000302:isolation & purification / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D032413:Viola / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047169:Cyclotides; D010456:Peptides, Cyclic; C473354:varv A; C473353:varv F; C473355:cycloviolacin O2