Role of labile iron in the toxicity of pharmacological ascorbate |
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Affiliation: | 1. Department of Biophysics of Environmental Pollution, University of Lodz, Lodz, Poland;2. Department of Hypertension, Medical University of Lodz, Lodz, Poland;3. Institute of Industrial Organic Chemistry, Warsaw, Poland;1. Department of Chemical and Materials Engineering, Chang Gung University, Kwei-Shan 33302, Taoyuan, Taiwan;2. Department of Chemical Engineering and Materials Science, Yuan Ze University, Chung-Li 32003, Taoyuan, Taiwan |
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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 2 mM 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., Fe3+/Fe2+, have an important role in ascorbate-induced cytotoxicity. Approaches that increase catalytic iron could potentially enhance the cytotoxicity of pharmacological ascorbate in vivo. |
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Keywords: | Asc-2P" },{" #name" :" keyword" ," $" :{" id" :" key0010" }," $$" :[{" #name" :" text" ," _" :" ascorbate-2-phosphate DFO" },{" #name" :" keyword" ," $" :{" id" :" key0020" }," $$" :[{" #name" :" text" ," _" :" deferoxamine DHA" },{" #name" :" keyword" ," $" :{" id" :" key0030" }," $$" :[{" #name" :" text" ," _" :" dehydroascorbic acid DPD" },{" #name" :" keyword" ," $" :{" id" :" key0040" }," $$" :[{" #name" :" text" ," _" :" 2,2′-dipyridyl 8-HQ" },{" #name" :" keyword" ," $" :{" id" :" key0050" }," $$" :[{" #name" :" text" ," _" :" 8-hydroxyquinoline DTPA" },{" #name" :" keyword" ," $" :{" id" :" key9060" }," $$" :[{" #name" :" text" ," _" :" diethylenetriaminepentaacetic acid PG SK" },{" #name" :" keyword" ," $" :{" id" :" key0060" }," $$" :[{" #name" :" text" ," _" :" Phen Green SK diacetate |
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