Journal article
Dual Oxidase-Induced Sustained Generation of Hydrogen Peroxide Contributes to Pharmacologic Ascorbate-Induced Cytotoxicity
Cancer research (Chicago, Ill.), Vol.80(7), pp.1401-1413
04/01/2020
DOI: 10.1158/0008-5472.CAN-19-3094
PMCID: PMC7127976
PMID: 32041838
Abstract
Pharmacologic ascorbate treatment (P-AscH
, high-dose, intravenous vitamin C) results in a transient short-term increase in the flux of hydrogen peroxide that is preferentially cytotoxic to cancer cells versus normal cells. This study examines whether an increase in hydrogen peroxide is sustained posttreatment and potential mechanisms involved in this process. Cellular bioenergetic profiling following treatment with P-AscH
was examined in tumorigenic and nontumorigenic cells. P-AscH
resulted in sustained increases in the rate of cellular oxygen consumption (OCR) and reactive oxygen species (ROS) in tumor cells, with no changes in nontumorigenic cells. Sources for this increase in ROS and OCR were DUOX 1 and 2, which are silenced in pancreatic ductal adenocarcinoma, but upregulated with P-AscH
treatment. An inducible catalase system, to test causality for the role of hydrogen peroxide, reversed the P-AscH
-induced increases in DUOX, whereas DUOX inhibition partially rescued P-AscH
-induced toxicity. In addition, DUOX was significantly downregulated in pancreatic cancer specimens compared with normal pancreas tissues. Together, these results suggest that P-AscH
-induced toxicity may be enhanced by late metabolic shifts in tumor cells, resulting in a feed-forward mechanism for generation of hydrogen peroxide and induction of metabolic stress through enhanced DUOX expression and rate of oxygen consumption. SIGNIFICANCE: A high dose of vitamin C, in addition to delivering an acute exposure of H
O
to tumor cells, activates DUOX in pancreatic cancer cells, which provide sustained production of H
O
.
Details
- Title: Subtitle
- Dual Oxidase-Induced Sustained Generation of Hydrogen Peroxide Contributes to Pharmacologic Ascorbate-Induced Cytotoxicity
- Creators
- Adrienne R Gibson - University of IowaBrianne R O'Leary - University of IowaJuan Du - University of IowaEhab H Sarsour - Kansas City UniversityAmanda L Kalen - University of IowaBrett A Wagner - University of IowaJeffrey M Stolwijk - Roy J. and Lucille A. Carver College of MedicineKelly C Falls-Hubert - University of IowaMatthew S Alexander - Roy J. and Lucille A. Carver College of MedicineRory S Carroll - University of IowaDouglas R Spitz - Roy J. and Lucille A. Carver College of MedicineGarry R Buettner - Roy J. and Lucille A. Carver College of MedicinePrabhat C Goswami - University of IowaJoseph J Cullen - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.80(7), pp.1401-1413
- DOI
- 10.1158/0008-5472.CAN-19-3094
- PMID
- 32041838
- PMCID
- PMC7127976
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Grant note
- P30 ES005605 / NIEHS NIH HHS F30 CA213817 / NCI NIH HHS P01 CA217797 / NCI NIH HHS T32 GM007337 / NIGMS NIH HHS R01 CA184051 / NCI NIH HHS R01 CA182804 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA169046 / NCI NIH HHS P50 CA174521 / NCI NIH HHS
- Language
- English
- Date published
- 04/01/2020
- Academic Unit
- Molecular Physiology and Biophysics; Pathology; Surgery; Radiation Oncology; Radiation Research Laboratory; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984312973002771
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