title: Increased generation of intracellular reactive oxygen species initiates selective cytotoxicity against the MCF-7 cell line resultant from redox active combination therapy using copper-thiosemicarbazone complexes.
abstract: The combination of cytotoxic copper-thiosemicarbazone complexes with phenoxazines results in an up to 50-fold enhancement in the cytotoxic potential of the thiosemicarbazone against the MCF-7 human breast adenocarcinoma cell line over the effect attributable to drug additivity-allowing minimization of the more toxic copper-thiosemicarbazone component of the therapy. The combination of a benzophenoxazine with all classes of copper complex examined in this study proved more effective than combinations of the copper complexes with related isoelectronic azines. The combination approach results in rapid elevation of intracellular reactive oxygen levels followed by apoptotic cell death. Normal fibroblasts representative of non-cancerous cells (MRC-5) did not display a similar elevation of reactive oxygen levels when exposed to similar drug levels. The minimization of the copper-thiosemicarbazone component of the therapy results in an enhanced safety profile against normal fibroblasts.
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Orange, NSW, 2800, Australia.
authors.forename: Fady N
authors.initials: FN
authors.lastname: Akladios
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Orange, NSW, 2800, Australia.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Andrew
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Orange, NSW, 2800, Australia. cparkinson@csu.edu.au.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Parkinson
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D009942:Organometallic Compounds; D010078:Oxazines; D017382:Reactive Oxygen Species; D013882:Thiosemicarbazones; D003300:Copper; C039203:phenoxazine
keywords: Benzophenoxazine; Copper; Cytotoxicity; Reactive oxygen species (ROS); Thiosemicarbazone