DOI

10.17077/etd.pigq0emi

Document Type

Thesis

Date of Degree

Summer 2018

Access Restrictions

Access restricted until 08/31/2020

Degree Name

MS (Master of Science)

Degree In

Free Radical and Radiation Biology

First Advisor

Cullen, Joseph J

First Committee Member

Spitz, Douglas R

Second Committee Member

Buettner, Garry R

Abstract

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-.

Keywords

Cancer, Pancreas, Pharmacological Ascorbate, Vitamin C

Pages

viii, 49 pages

Bibliography

Includes bibliographical references (pages 45-49).

Copyright

Copyright © 2018 Adrienne Rae Gibson

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