Catalase Modulates the Radio-Sensitization of Pancreatic Cancer Cells by Pharmacological Ascorbate
Pancreatic cancer cells (PDACs) are more susceptible to an oxidative insult than normal cells, resulting in greater cytotoxicity upon exposure to agents that increase pro-oxidant levels. Pharmacological ascorbate (P-AscH<sup>−</sup>), i.e., large amounts given intravenously (IV), generat...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-04-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/4/614 |
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| author | Juan Du Rory S. Carroll Garett J. Steers Brett A. Wagner Brianne R. O’Leary Chris S. Jensen Garry R. Buettner Joseph J. Cullen |
| author_facet | Juan Du Rory S. Carroll Garett J. Steers Brett A. Wagner Brianne R. O’Leary Chris S. Jensen Garry R. Buettner Joseph J. Cullen |
| author_sort | Juan Du |
| collection | DOAJ |
| description | Pancreatic cancer cells (PDACs) are more susceptible to an oxidative insult than normal cells, resulting in greater cytotoxicity upon exposure to agents that increase pro-oxidant levels. Pharmacological ascorbate (P-AscH<sup>−</sup>), i.e., large amounts given intravenously (IV), generates significant fluxes of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), resulting in the killing of PDACs but not normal cells. Recent studies have demonstrated that P-AscH<sup>−</sup> radio-sensitizes PDAC but is a radioprotector to normal cells and tissues. Several mechanisms have been hypothesized to explain the dual roles of P-AscH<sup>−</sup> in radiation-induced toxicity including the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2), RelB, as well as changes in bioenergetic profiles. We have found that P-AscH<sup>−</sup> in conjunction with radiation increases Nrf2 in both cancer cells and normal cells. Although P-AscH<sup>−</sup> with radiation decreases RelB in cancer cells vs. normal cells, the knockout of RelB does not radio-sensitize PDACs. Cellular bioenergetic profiles demonstrate that P-AscH<sup>−</sup> with radiation increases the ATP demand/production rate (glycolytic and oxidative phosphorylation) in both PDACs and normal cells. Knocking out catalase results in P-AscH<sup>−</sup> radio-sensitization in PDACs. In a phase I trial where P-AscH<sup>−</sup> was included as an adjuvant to the standard of care, short-term survivors had higher catalase levels in tumor tissue, compared to long-term survivors. These data suggest that P-AscH<sup>−</sup> radio-sensitizes PDACs through increased peroxide flux. Catalase levels could be a possible indicator for how tumors will respond to P-AscH<sup>−</sup>. |
| first_indexed | 2024-03-10T12:15:21Z |
| format | Article |
| id | doaj.art-5d368059696c4251aebd2719099c0cd8 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T12:15:21Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-5d368059696c4251aebd2719099c0cd82023-11-21T15:52:24ZengMDPI AGAntioxidants2076-39212021-04-0110461410.3390/antiox10040614Catalase Modulates the Radio-Sensitization of Pancreatic Cancer Cells by Pharmacological AscorbateJuan Du0Rory S. Carroll1Garett J. Steers2Brett A. Wagner3Brianne R. O’Leary4Chris S. Jensen5Garry R. Buettner6Joseph J. Cullen7Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USAFree Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USAFree Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USADepartment of Surgery, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USAFree Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USADepartment of Pathology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USADepartment of Surgery, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USAFree Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USAPancreatic cancer cells (PDACs) are more susceptible to an oxidative insult than normal cells, resulting in greater cytotoxicity upon exposure to agents that increase pro-oxidant levels. Pharmacological ascorbate (P-AscH<sup>−</sup>), i.e., large amounts given intravenously (IV), generates significant fluxes of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), resulting in the killing of PDACs but not normal cells. Recent studies have demonstrated that P-AscH<sup>−</sup> radio-sensitizes PDAC but is a radioprotector to normal cells and tissues. Several mechanisms have been hypothesized to explain the dual roles of P-AscH<sup>−</sup> in radiation-induced toxicity including the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2), RelB, as well as changes in bioenergetic profiles. We have found that P-AscH<sup>−</sup> in conjunction with radiation increases Nrf2 in both cancer cells and normal cells. Although P-AscH<sup>−</sup> with radiation decreases RelB in cancer cells vs. normal cells, the knockout of RelB does not radio-sensitize PDACs. Cellular bioenergetic profiles demonstrate that P-AscH<sup>−</sup> with radiation increases the ATP demand/production rate (glycolytic and oxidative phosphorylation) in both PDACs and normal cells. Knocking out catalase results in P-AscH<sup>−</sup> radio-sensitization in PDACs. In a phase I trial where P-AscH<sup>−</sup> was included as an adjuvant to the standard of care, short-term survivors had higher catalase levels in tumor tissue, compared to long-term survivors. These data suggest that P-AscH<sup>−</sup> radio-sensitizes PDACs through increased peroxide flux. Catalase levels could be a possible indicator for how tumors will respond to P-AscH<sup>−</sup>.https://www.mdpi.com/2076-3921/10/4/614pharmacological ascorbateDNA damageDNA repairpancreatic cancervitamin C |
| spellingShingle | Juan Du Rory S. Carroll Garett J. Steers Brett A. Wagner Brianne R. O’Leary Chris S. Jensen Garry R. Buettner Joseph J. Cullen Catalase Modulates the Radio-Sensitization of Pancreatic Cancer Cells by Pharmacological Ascorbate Antioxidants pharmacological ascorbate DNA damage DNA repair pancreatic cancer vitamin C |
| title | Catalase Modulates the Radio-Sensitization of Pancreatic Cancer Cells by Pharmacological Ascorbate |
| title_full | Catalase Modulates the Radio-Sensitization of Pancreatic Cancer Cells by Pharmacological Ascorbate |
| title_fullStr | Catalase Modulates the Radio-Sensitization of Pancreatic Cancer Cells by Pharmacological Ascorbate |
| title_full_unstemmed | Catalase Modulates the Radio-Sensitization of Pancreatic Cancer Cells by Pharmacological Ascorbate |
| title_short | Catalase Modulates the Radio-Sensitization of Pancreatic Cancer Cells by Pharmacological Ascorbate |
| title_sort | catalase modulates the radio sensitization of pancreatic cancer cells by pharmacological ascorbate |
| topic | pharmacological ascorbate DNA damage DNA repair pancreatic cancer vitamin C |
| url | https://www.mdpi.com/2076-3921/10/4/614 |
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