Genotoxicity and Cellular Uptake of Cyclotides: Evidence for Multiple Mode of Action
2012 (English)In: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, Vol. 747, no 2, 176-181 p.Article in journal (Refereed) Published
Cyclotides are a family of ultra stable, head-to-tail cyclic plant mini-proteins with each member comprising about 30 amino acid residues. Their stability is associated with the unique structural topology where the cyclic backbone and two disulfide bonds make up an embedded ring which is knotted by a third disulfide bond. The cyclotides find potential applications in drug industry as a drug scaffolds for unstable drugs and also as medicinal agents due to the wide range of inherent pharmacological activities they possess. However, there is a lack of fundamental toxicological studies on these classes of compounds. The current study determined a possible DNA damaging effect of three cyclotides, i.e., cycloviolacin O2, vaby D, and kalata B1 in human lymphoma cells using the alkaline version of the comet assay. The three cyclotides induced massive DNA fragmentation at lethal concentrations. At a sublethal concentration, cycloviolacin O2 and vaby D gave a bell shaped dose-response curve for their DNA-damaging effect. Kalata B1 caused no significant DNA damage at sub cytotoxic concentrations. Single cell microautoradiography was carried out on tritium labeled cycloviolacin O2 in order to understand the mechanism behind the dose-response curve. The results revealed that the peptide is taken up into the cell, at both cytotoxic and at low concentrations. Most biological effects of the cyclotides have been taken to follow from the disruption of cell membranes, but even if the intracellular mechanisms/targets still remain unknown, the current study has unequivocally demonstrated that these compounds also must have other dose-dependent modes of action.
Place, publisher, year, edition, pages
2012. Vol. 747, no 2, 176-181 p.
cyclotide, cycloviolacin O2, vaby D, kalata B1, comet assay, DNA damage, microautoradiography, mode of action, viola odorata, viola abyssinica, oldenlandia affinis, cell penetrating, radiolabeling
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-171150DOI: 10.1016/j.mrgentox.2012.05.006ISI: 000307148600003OAI: oai:DiVA.org:uu-171150DiVA: diva2:510262