Document Detail


Inhibitors of hydroperoxide metabolism enhance ascorbate-induced cytotoxicity.
MedLine Citation:
PMID:  23205739     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Pharmacological ascorbate, via its oxidation, has been proposed as a pro-drug for the delivery of H(2)O(2) to tumors. Pharmacological ascorbate decreases clonogenic survival of pancreatic cancer cells, which can be reversed by treatment with scavengers of H(2)O(2). The goal of this study was to determine if inhibitors of intracellular hydroperoxide detoxification could enhance the cytotoxic effects of ascorbate. Human pancreatic cancer cells were treated with ascorbate alone or in combination with inhibitors of hydroperoxide removal including the glutathione disulfide reductase inhibitor 1,3 bis (2-chloroethyl)-1-nitrosurea (BCNU), siRNA targeted to glutathione disulfide reductase (siGR), and 2-deoxy-D-glucose (2DG), which inhibits glucose metabolism. Changes in the intracellular concentration of H(2)O(2) were determined by analysis of the rate of aminotriazole-mediated inactivation of endogenous catalase activity. Pharmacological ascorbate increased intracellular H(2)O(2) and depleted intracellular glutathione. When inhibitors of H(2)O(2) metabolism were combined with pharmacological ascorbate the increase in intracellular H(2)O(2) was amplified and cytotoxicity was enhanced. We conclude that inclusion of agents that inhibit cellular peroxide removal produced by pharmacological ascorbate leads to changes in the intracellular redox state resulting in enhanced cytotoxicity.
Authors:
K E Olney; J Du; T J van 't Erve; J R Witmer; Z A Sibenaller; B A Wagner; G R Buettner; J J Cullen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-01-09
Journal Detail:
Title:  Free radical research     Volume:  47     ISSN:  1029-2470     ISO Abbreviation:  Free Radic. Res.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-08     Completed Date:  2013-07-15     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9423872     Medline TA:  Free Radic Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  154-63     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amitrole / pharmacology*
Antineoplastic Agents / pharmacology*
Ascorbic Acid / pharmacology*
Carmustine / pharmacology
Catalase / antagonists & inhibitors*,  metabolism
Cell Line, Tumor
Cell Survival / drug effects
Drug Screening Assays, Antitumor
Drug Synergism
Gene Knockdown Techniques
Glutathione Disulfide / metabolism
Glutathione Reductase / antagonists & inhibitors,  genetics,  metabolism
Humans
Hydrogen Peroxide / metabolism*
Oxidation-Reduction
Oxidative Stress / drug effects
RNA, Small Interfering / genetics
Grant Support
ID/Acronym/Agency:
P30 ES005605/ES/NIEHS NIH HHS; P42 ES013661/ES/NIEHS NIH HHS; R01 GM073929/GM/NIGMS NIH HHS; R01GM073929/GM/NIGMS NIH HHS; T32CA078586/CA/NCI NIH HHS; U01 CA166800/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/RNA, Small Interfering; BBX060AN9V/Hydrogen Peroxide; EC 1.11.1.6/Catalase; EC 1.8.1.7/Glutathione Reductase; PQ6CK8PD0R/Ascorbic Acid; U68WG3173Y/Carmustine; ULW86O013H/Glutathione Disulfide; ZF80H5GXUF/Amitrole
Comments/Corrections

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