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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| Format: | Article |
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MDPI AG
2023-08-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/9/1683 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Garett J. Steers |
| collection | DOAJ |
| 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<sub>2</sub>O<sub>2</sub>) in normal pancreatic tissue but are silenced in pancreatic cancer (PDAC). Treatment of PDAC with pharmacologic ascorbate (P-AscH<sup>−</sup>, intravenous, high dose vitamin C) increases DUOX expression. We hypothesized that inhibiting DNMT may act synergistically with P-AscH<sup>−</sup> 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<sup>−</sup> + 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. |
| first_indexed | 2024-03-10T23:06:18Z |
| format | Article |
| id | doaj.art-43fcb3ed3d244d5f89e306ce3c3698cf |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T23:06:18Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-43fcb3ed3d244d5f89e306ce3c3698cf2023-11-19T09:18:57ZengMDPI AGAntioxidants2076-39212023-08-01129168310.3390/antiox12091683Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic CancerGarett J. Steers0Brianne R. O’Leary1Juan Du2Brett A. Wagner3Rory S. Carroll4Frederick E. Domann5Prabhat C. Goswami6Garry R. Buettner7Joseph J. Cullen8Free Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USAFree Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USAFree Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USAFree Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USAFree Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USAFree Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USAFree Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USAFree Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USAFree Radical and Radiation Biology Division, Department of Radiation Oncology, Iowa City, IA 52242, USARecent 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<sub>2</sub>O<sub>2</sub>) in normal pancreatic tissue but are silenced in pancreatic cancer (PDAC). Treatment of PDAC with pharmacologic ascorbate (P-AscH<sup>−</sup>, intravenous, high dose vitamin C) increases DUOX expression. We hypothesized that inhibiting DNMT may act synergistically with P-AscH<sup>−</sup> 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<sup>−</sup> + 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.https://www.mdpi.com/2076-3921/12/9/1683ascorbic acidpharmacologic ascorbatepancreatic cancerepigeneticsDNA methyltransferase (DNMT)ten-eleven translocation (TET) methylcytosine dioxygenase |
| spellingShingle | 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 Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer Antioxidants ascorbic acid pharmacologic ascorbate pancreatic cancer epigenetics DNA methyltransferase (DNMT) ten-eleven translocation (TET) methylcytosine dioxygenase |
| 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 | ascorbic acid pharmacologic ascorbate pancreatic cancer epigenetics DNA methyltransferase (DNMT) ten-eleven translocation (TET) methylcytosine dioxygenase |
| url | https://www.mdpi.com/2076-3921/12/9/1683 |
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