Cyclotides: a novel type of cytotoxic agents.
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.
Lindholm
Petra
P
Division of Pharmacognosy, Department of Medicinal Chemistry, BMC, Uppsala University, Sweden.
Göransson
Ulf
U
Johansson
Senia
S
Claeson
Per
P
Gullbo
Joachim
J
Larsson
Rolf
R
Bohlin
Lars
L
Backlund
Anders
A
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
D000972:Antineoplastic Agents, Phytogenic; D047169:Cyclotides; D010456:Peptides, Cyclic; C473354:varv A; C473353:varv F; C473355:cycloviolacin O2