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

Back

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

Journal article

Open access

Peer reviewed

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 and Joseph J. Cullen

Antioxidants, Vol.12(9), p.1683

08/29/2023

DOI: 10.3390/antiox12091683

PMCID: PMC10525653

PMID: 37759986

Files and links (1)

url

https://doi.org/10.3390/antiox12091683View

Published (Version of record) Open Access

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.

Details

Title: Subtitle: Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer
Creators: Garett J. Steers - University of Iowa
Brianne R. O’Leary - University of Iowa
Juan Du - University of Iowa
Brett A. Wagner - University of Iowa
Rory S. Carroll - University of Iowa
Frederick E. Domann - University of Iowa
Prabhat C. Goswami - University of Iowa
Garry R. Buettner - University of Iowa
Joseph J. Cullen - University of Iowa
Resource Type: Journal article
Publication Details: Antioxidants, Vol.12(9), p.1683
DOI: 10.3390/antiox12091683
PMID: 37759986
PMCID: PMC10525653
NLM abbreviation: Antioxidants (Basel)
ISSN: 2076-3921
eISSN: 2076-3921
Grant note: name: National Institute of Health, award: P01 CA217797, T32 CA148062
Language: English
Date published: 08/29/2023
Academic Unit: Surgery; Radiation Oncology
Record Identifier: 9984459659702771

Metrics

13 Record Views

2 Times Cited - Web of Science

See more details