title: Mixed chelate copper complex, Casiopeina IIgly, binds and degrades nucleic acids: a mechanism of cytotoxicity.
abstract: Metal-containing drugs that interact with DNA have been designed and studied for their anticancer activity. In this study, the mixed chelate copper-based anticancer drugs, the casiopeinas, were found to bind to DNA and to degrade DNA and RNA in the presence of reducing agents (e.g. ascorbic acid). Casiopeinas binding to DNA is high affinity, with harsh wash conditions failing to remove the interaction. The reaction requires oxygen, probably involved in the generation of *OH radicals, which would be responsible for the strand breakage. The reaction was diminished by catalase, and was completely abolished by copper chelators (e.g. trientine, EDTA); however, superoxide dismutase (SOD) had no significant effect on casiopeina-mediated DNA degradation. Casiopeina IIgly (casIIgly) in the presence of ascorbate was capable of degrading RNA, plasmid and genomic DNA, and chromatin and intranuclear genetic material. Moreover, catalase and/or SOD partially protected cells, ascorbic acid enhanced and trientine, a copper chelator, abolished the cytotoxicity of casIIgly. The generation of 8-oxodG in cells exposed to casIIgly suggests that the generation of ROS is the major cause of the cytotoxicity observed and underlies the high toxicity and anticancer activity of these compounds.
authors.affiliation: School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey GU2 5XH, UK. adoriv@utu.fi
authors.forename: Adolfo
authors.initials: A
authors.lastname: Rivero-Müller
authors.forename: Andrea
authors.initials: A
authors.lastname: De Vizcaya-Ruiz
authors.forename: Nick
authors.initials: N
authors.lastname: Plant
authors.forename: Lena
authors.initials: L
authors.lastname: Ruiz
authors.forename: Miloslav
authors.initials: M
authors.lastname: Dobrota
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000737:chemistry / Q000494:pharmacology; D019556:COS Cells; D002374:Catalase / Q000378:metabolism; D002522:Chlorocebus aethiops; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers; D006801:Humans; D009696:Nucleic Acids / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D010618:Phenanthrolines / Q000737:chemistry; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D009696:Nucleic Acids; D009942:Organometallic Compounds; D010618:Phenanthrolines; C505569:casiopeina II-glycine; D004247:DNA; D002374:Catalase; D013482:Superoxide Dismutase; D001205:Ascorbic Acid