Pharmacologic Ascorbate and Dnmt Inhibitors Increase Duox Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer

Garett J. Steers; Brianne R. O’Leary; Juan Du; Brett A. Wagner; Rory S. Carroll; Frederick E. Domann; Prabhat C. Goswami; Garry R. Buettner; Joseph J. Cullen

doi:10.20944/preprints202307.1251.v1

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preprints.org > medicine and pharmacology > oncology and oncogenics > doi: 10.20944/preprints202307.1251.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Pharmacologic Ascorbate and Dnmt Inhibitors Increase Duox Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer

Version 1 : Received: 17 July 2023 / Approved: 18 July 2023 / Online: 18 July 2023 (13:51:14 CEST)

A peer-reviewed article of this Preprint also exists.

Steers, G.J.; O’Leary, B.R.; Du, J.; Wagner, B.A.; Carroll, R.S.; Domann, F.E.; Goswami, P.C.; Buettner, G.R.; Cullen, J.J. Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer. Antioxidants 2023, 12, 1683. Steers, G.J.; O’Leary, B.R.; Du, J.; Wagner, B.A.; Carroll, R.S.; Domann, F.E.; Goswami, P.C.; Buettner, G.R.; Cullen, J.J. Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer. Antioxidants 2023, 12, 1683.

Abstract

Recent studies have demonstrated an important role for vitamin C in the epigenetic regulation of cancer-related genes via DNA demethylation by the ten-eleven translocation (TET) methylcytosine dioxygenase enzymes. DNA methyltransferase (DNMT) reverses this, increasing DNA methylation and decreasing gene expression. Dual oxidase (DUOX) enzymes produce hydrogen peroxide (H2O2) in normal pancreatic tissue but are silenced in pancreatic cancer (PDAC). Treatment of PDAC with pharmacologic ascorbate (P-AscH-, intravenous, high dose vitamin C) increases DUOX expression. We hypothesized that inhibiting DNMT may act synergistically with P-AscH- to further increase DUOX expression and cytotoxicity of PDAC. PDAC cells demonstrated dose-dependent increases in DUOX mRNA and protein expression when treated with DNMT inhibitors. PDAC cells treated with P-AscH- + DNMT inhibitors demonstrated increased DUOX expression, increased intracellular oxidation, and increased cytotoxicity in vitro and in vivo compared to either treatment alone. These findings suggest a potential therapeutic, epigenetic mechanism to treat PDAC.

Keywords

ascorbic acid; pharmacologic ascorbate; pancreatic cancer; epigenetics; DNA methyltransferase (DNMT); ten-eleven translocation (TET) methylcytosine dioxygenase

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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