title: Mechanisms underlying reductant-induced reactive oxygen species formation by anticancer copper(II) compounds.
abstract: Intracellular generation of reactive oxygen species (ROS) via thiol-mediated reduction of copper(II) to copper(I) has been assumed as the major mechanism underlying the anticancer activity of copper(II) complexes. The aim of this study was to compare the anticancer potential of copper(II) complexes of Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; currently in phase II clinical trials) and its terminally dimethylated derivative with that of 2-formylpyridine thiosemicarbazone and that of 2,2'-bipyridyl-6-carbothioamide. Experiments on generation of oxidative stress and the influence of biologically relevant reductants (glutathione, ascorbic acid) on the anticancer activity of the copper complexes revealed that reductant-dependent redox cycling occurred mainly outside the cells, leading to generation and dismutation of superoxide radicals resulting in cytotoxic amounts of H(2)O(2). However, without extracellular reductants only weak intracellular ROS generation was observed at IC(50) levels, suggesting that cellular thiols are not involved in copper-complex-induced oxidative stress. Taken together, thiol-induced intracellular ROS generation might contribute to the anticancer activity of copper thiosemicarbazone complexes but is not the determining factor.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Austria.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Kowol
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.forename: Walter
authors.initials: W
authors.lastname: Miklos
authors.forename: Lars
authors.initials: L
authors.lastname: Gille
authors.forename: Robert
authors.initials: R
authors.lastname: Trondl
authors.forename: Loredana
authors.initials: L
authors.lastname: Cappellacci
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004563:Electrochemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D013882:Thiosemicarbazones; C066363:copper-thiosemicarbazone complex