Date of Degree
Access restricted until 08/31/2020
MS (Master of Science)
Free Radical and Radiation Biology
Cullen, Joseph J
First Committee Member
Spitz, Douglas R
Second Committee Member
Buettner, Garry R
Pharmacological ascorbate treatment (P-AscH-, high-dose, intravenous vitamin C) results in a short-term increased flux of H2O2 that is preferentially cytotoxic to cancer cells vs. normal cells. We hypothesized that there may be a sustained effect (> 24 h) of P-AscH- that may contribute to cytotoxicity. P-AscH- significantly increased sustained oxygen consumption (OCR), DCFH-DA oxidation, and extracellular acidification (ECAR) in tumor lines with no change in non-tumorigenic cells. One possible source of this sustained ROS and OCR, the NADPH oxidase family of enzymes Dual Oxidase 1 and 2 (DUOX), which are epigenetically silenced by methylation in vitro and in vivo in PDAC, are up-regulated with P-AscH- treatment. Catalase pretreatment reversed the P-AscH--induced increases in DUOX, while DUOX inhibition partially rescues P-AscH- toxicity. Additionally, nutritional ascorbate is unable to mediate the increase in DUOX expression. Together these results suggest that P-AscH--induced toxicity may be enhanced by late metabolic and epigenetic shifts in tumor cells resulting in a feed-forward mechanism of H2O2 generation and induction of metabolic stress via enhanced DUOX expression and OCR. These data highlight a novel epigenetic mechanism of action for P-AscH-.
Cancer, Pancreas, Pharmacological Ascorbate, Vitamin C
viii, 49 pages
Includes bibliographical references (pages 45-49).
Copyright © 2018 Adrienne Rae Gibson
Gibson, Adrienne Rae. "Pharmacological ascorbate enhances oxygen consumption and epigenetic reprogramming in pancreatic cancer." MS (Master of Science) thesis, University of Iowa, 2018.