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:10.3390/antiox12091683

Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer

Antioxidants (Basel). 2023 Aug 29;12(9):1683. doi: 10.3390/antiox12091683.

Authors

Garett J Steers^{1

2}, Brianne R O'Leary^{1

2}, Juan Du^{1

2}, Brett A Wagner¹, Rory S Carroll^{1

2}, Frederick E Domann¹, Prabhat C Goswami¹, Garry R Buettner¹, Joseph J Cullen^{1

2}

Affiliations

¹ Free Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USA.
² The Department of Surgery, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.

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

Abstract

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