title: DNA binding and oxidative DNA damage induced by climacostol-copper(II) complexes: implications for anticancer properties.
abstract: Climacostol is a natural toxin isolated from the freshwater ciliated protozoan Climacostomum virens and belongs to the group of resorcinolic lipids. Climacostol exerts a potent antimicrobial activity against a panel of bacterial and fungal pathogens. In addition it inhibits the growth of tumor cell lines in a dose-dependent manner by inducing programmed cell death via intrinsic pathway. In this work, we investigated the possibility that climacostol exerts a prooxidant effect, inducing plasmid DNA strand breakage and eukaryotic DNA damage in presence of Cu(II) ions. Inhibition of DNA breakage using SOD, catalase and neocuproine confirmed the involvement of reactive oxygen species and Cu(I) ions in the DNA damage. UV-visible absorption changes and mass spectrometric analysis identified a product of reaction as a deprotonated form of climacostol. Study of the interaction with DNA, using fluorescence spectroscopic techniques, showed that climacostol binds with DNA. Given the structure-activity relationship of this compound and the mechanism of its prooxidant effect, we propose that the Cu(II)-mediated oxidative DNA damage by climacostol could explain its antimicrobial and antiproliferative activity.
authors.affiliation: School of Pharmacy, Section of Physiology, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Quassinti
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortenzi
authors.forename: Enrico
authors.initials: E
authors.lastname: Marcantoni
authors.forename: Massimo
authors.initials: M
authors.lastname: Ricciutelli
authors.forename: Giulio
authors.initials: G
authors.lastname: Lupidi
authors.forename: Claudio
authors.initials: C
authors.lastname: Ortenzi
authors.forename: Federico
authors.initials: F
authors.lastname: Buonanno
authors.forename: Massimo
authors.initials: M
authors.lastname: Bramucci
mesh_terms: D000838:Anions / Q000032:analysis; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000737:chemistry*; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004249:DNA Damage; D005609:Free Radicals / Q000032:analysis; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010957:Plasmids; D012118:Resorcinols / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D013481:Superoxides / Q000032:analysis
chemical_list: D000838:Anions; D000970:Antineoplastic Agents; D005609:Free Radicals; D009942:Organometallic Compounds; D012118:Resorcinols; C453475:climacostol; D013481:Superoxides; D003300:Copper; D004247:DNA
keywords: Climacostol; Copper; DNA damage; Reactive oxygen species