Journal article
INHIBITORS OF HYDROPEROXIDE METABOLISM ENHANCE ASCORBATE-INDUCED CYTOTOXICITY
Free radical research, Vol.47(3), pp.154-163
03/2013
DOI: 10.3109/10715762.2012.755263
PMCID: PMC3674878
PMID: 23205739
Abstract
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.
Details
- Title: Subtitle
- INHIBITORS OF HYDROPEROXIDE METABOLISM ENHANCE ASCORBATE-INDUCED CYTOTOXICITY
- Creators
- Kristen E OlneyJuan DuThomas J van 't ErveJordan R WitmerZita A SibenallerBrett A WagnerGarry R BuettnerJoseph J Cullen
- Resource Type
- Journal article
- Publication Details
- Free radical research, Vol.47(3), pp.154-163
- DOI
- 10.3109/10715762.2012.755263
- PMID
- 23205739
- PMCID
- PMC3674878
- ISSN
- 1071-5762
- eISSN
- 1029-2470
- Grant note
- U01 CA166800 || CA / National Cancer Institute : NCI
- Language
- English
- Date published
- 03/2013
- Academic Unit
- Stead Family Department of Pediatrics; Surgery; Radiation Oncology; Hospital Medicine
- Record Identifier
- 9984047988702771
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