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

Available for download on Monday, August 31, 2020

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