title: Redox catalysts as sensitisers towards oxidative stress.
abstract: The predominance of oxidative stress in many tumour cell environments provides a means to selectively target these cells via protein oxidation. The zinc fingers of transcription factors utilise cysteine thiols for structural zinc coordination. Redox control of DNA binding regulates transcription and therefore the overall rates of proliferation, apoptosis and necrosis in the carcinoma. We report here the adverse effects of glutathione peroxidase (GPx) mimics towards zinc finger motifs and PC12 cell survival. Nanomolar catalyst concentrations facilitated H2O2-induced oxidation of an Sp1 transcription factor fragment. In PC12 cells GPx catalysis triggered a significant increase in cell death, correlating with severity of oxidative stress. As a consequence, we conclude that GPx mimics are potential chemotherapeutic agents.
authors.affiliation: School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK.
authors.forename: Niroshini M
authors.initials: NM
authors.lastname: Giles
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Gutowski
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Giles
authors.forename: Claus
authors.initials: C
authors.lastname: Jacob
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology; D002384:Catalysis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018011:Chalcogens / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005979:Glutathione Peroxidase; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000494:pharmacology*; D054833:Isoindoles; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D016566:Organoselenium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000494:pharmacology; D012643:Selenium / Q000737:chemistry; D016329:Sp1 Transcription Factor / Q000737:chemistry; D013691:Tellurium / Q000737:chemistry; D016335:Zinc Fingers / Q000187:drug effects
chemical_list: D000975:Antioxidants; D001393:Azoles; D018011:Chalcogens; D054833:Isoindoles; D009942:Organometallic Compounds; D016566:Organoselenium Compounds; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D016329:Sp1 Transcription Factor; C042986:ebselen; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D012643:Selenium; D013691:Tellurium