Role of labile iron in the toxicity of pharmacological ascorbate

Juan Du; Brett A Wagner; Garry R Buettner; Joseph J Cullen

doi:10.1016/j.freeradbiomed.2015.03.033

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Role of labile iron in the toxicity of pharmacological ascorbate

Journal article

Open access

Peer reviewed

Role of labile iron in the toxicity of pharmacological ascorbate

Juan Du, Brett A Wagner, Garry R Buettner and Joseph J Cullen

Free radical biology & medicine, Vol.84, pp.289-295

07/2015

DOI: 10.1016/j.freeradbiomed.2015.03.033

PMCID: PMC4739508

PMID: 25857216

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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 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., 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. [Display omitted] •Catalytic metals are central in determining the rate of oxidation of ascorbate and production of H2O2.•Extracellular catalytic iron is vital to the cellular toxicity of pharmacological ascorbate.•Increasing intracellular labile iron enhances the toxicity of pharmacological ascorbate.

DTPA

8-HQ

Asc-2P

DPD

PG SK

DFO

DHA

Details

Title: Subtitle: Role of labile iron in the toxicity of pharmacological ascorbate
Creators: Juan Du - Department of Surgery, University of Iowa College of Medicine, Iowa City, IA 52242, USA
Brett A Wagner - Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa College of Medicine, Iowa City, IA 52242, USA
Garry R Buettner - Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa College of Medicine, Iowa City, IA 52242, USA
Joseph J Cullen - Department of Surgery, University of Iowa College of Medicine, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Free radical biology & medicine, Vol.84, pp.289-295
DOI: 10.1016/j.freeradbiomed.2015.03.033
PMID: 25857216
PMCID: PMC4739508
NLM abbreviation: Free Radic Biol Med
ISSN: 0891-5849
eISSN: 1873-4596
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100000002, name: NIH, award: U01 CA166800, R01 CA169046, R01 GM073929; name: Medical Research Service, Department of Veterans Affairs, award: 1I01BX001318-01A2; DOI: 10.13039/100000002, name: NIH, award: P30 CA086862
Language: English
Date published: 07/2015
Academic Unit: Surgery; Radiation Oncology
Record Identifier: 9984047987302771

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