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

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...

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Autores principales: Steers, Garett J., O’Leary, Brianne R., Du, Juan, Wagner, Brett A., Carroll, Rory S., Domann, Frederick E., Goswami, Prabhat C., Buettner, Garry R., Cullen, Joseph J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10525653/
https://www.ncbi.nlm.nih.gov/pubmed/37759986
http://dx.doi.org/10.3390/antiox12091683
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author Steers, Garett J.
O’Leary, Brianne R.
Du, Juan
Wagner, Brett A.
Carroll, Rory S.
Domann, Frederick E.
Goswami, Prabhat C.
Buettner, Garry R.
Cullen, Joseph J.
author_facet Steers, Garett J.
O’Leary, Brianne R.
Du, Juan
Wagner, Brett A.
Carroll, Rory S.
Domann, Frederick E.
Goswami, Prabhat C.
Buettner, Garry R.
Cullen, Joseph J.
author_sort Steers, Garett J.
collection PubMed
description 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 (H(2)O(2)) 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.
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spelling pubmed-105256532023-09-28 Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer Steers, Garett J. O’Leary, Brianne R. Du, Juan Wagner, Brett A. Carroll, Rory S. Domann, Frederick E. Goswami, Prabhat C. Buettner, Garry R. Cullen, Joseph J. Antioxidants (Basel) Article 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 (H(2)O(2)) 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. MDPI 2023-08-29 /pmc/articles/PMC10525653/ /pubmed/37759986 http://dx.doi.org/10.3390/antiox12091683 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Steers, Garett J.
O’Leary, Brianne R.
Du, Juan
Wagner, Brett A.
Carroll, Rory S.
Domann, Frederick E.
Goswami, Prabhat C.
Buettner, Garry R.
Cullen, Joseph J.
Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer
title Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer
title_full Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer
title_fullStr Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer
title_full_unstemmed Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer
title_short Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer
title_sort pharmacologic ascorbate and dnmt inhibitors increase duox expression and peroxide-mediated toxicity in pancreatic cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10525653/
https://www.ncbi.nlm.nih.gov/pubmed/37759986
http://dx.doi.org/10.3390/antiox12091683
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