title: Role of labile iron in the toxicity of pharmacological ascorbate.
abstract: Pharmacological ascorbate has been shown to induce toxicity in a wide range of cancer cell lines. Pharmacological ascorbate in animal models has shown promise for use in cancer treatment. At pharmacological concentrations the oxidation of ascorbate produces a high flux of H2O2 via the formation of ascorbate radical (Asc(•-)). The rate of oxidation of ascorbate is principally a function of the level of catalytically active metals. Iron in cell culture media contributes significantly to the rate of H2O2 generation. We hypothesized that increasing intracellular iron would enhance ascorbate-induced cytotoxicity and that iron chelators could modulate the catalytic efficiency with respect to ascorbate oxidation. Treatment of cells with the iron-chelators deferoxamine (DFO) or dipyridyl (DPD) in the presence of 2mM ascorbate decreased the flux of H2O2 generated by pharmacological ascorbate and reversed ascorbate-induced toxicity. Conversely, increasing the level of intracellular iron by preincubating cells with Fe-hydroxyquinoline (HQ) increased ascorbate toxicity and decreased clonogenic survival. These findings indicate that redox metal metals, e.g., Fe(3+)/Fe(2+), have an important role in ascorbate-induced cytotoxicity. Approaches that increase catalytic iron could potentially enhance the cytotoxicity of pharmacological ascorbate in vivo.
authors: Department of Surgery, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
authors: Juan
authors: J
authors: Du
authors: Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
authors: Brett A
authors: BA
authors: Wagner
authors: Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa College of Medicine, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Iowa City, IA, USA.
authors: Garry R
authors: GR
authors: Buettner
authors: Department of Surgery, University of Iowa College of Medicine, Iowa City, IA 52242, USA; Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa College of Medicine, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Iowa City, IA, USA; Veterans Affairs Medical Center, Iowa City, IA, USA. Electronic address: joseph-cullen@uiowa.edu.
authors: Joseph J
authors: JJ
authors: Cullen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004347:Drug Interactions; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D010084:Oxidation-Reduction
chemical_list: D000970:Antineoplastic Agents; D007502:Iron Chelating Agents; D006861:Hydrogen Peroxide; D007501:Iron; D001205:Ascorbic Acid