Pharmacologic Ascorbate Radiosensitizes Pancreatic Cancer but Radioprotects Normal Tissue: The Role of Oxidative Stress-Induced Lipid Peroxidation
| Autor: | Gloria Y. Chen, Brianne R. O’Leary, Juan Du, Rory S. Carroll, Garett J. Steers, Garry R. Buettner, Joseph J. Cullen |
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| Jazyk: | angličtina |
| Rok vydání: | 2024 |
| Předmět: | |
| Zdroj: | Antioxidants, Vol 13, Iss 3, p 361 (2024) |
| Druh dokumentu: | article |
| ISSN: | 13030361 2076-3921 |
| DOI: | 10.3390/antiox13030361 |
| Popis: | The toxicity of ionizing radiation limits its effectiveness in the treatment of pancreatic ductal adenocarcinoma. Pharmacologic ascorbate (P-AscH−) has been shown to radiosensitize pancreatic cancer cells while simultaneously radioprotecting normal cells. We hypothesize that P-AscH− protects the small intestine while radiosensitizing pancreatic cancer cells partially through an oxidative stress mechanism. Duodenal samples from pancreaticoduodenectomy specimens of patients who underwent radio-chemotherapy ± P-AscH− and mouse tumor and jejunal samples treated with radiation ± P-AscH− were evaluated. Pancreatic cancer and non-tumorigenic cells were treated with radiation ± P-AscH− to assess lipid peroxidation. To determine the mechanism, pancreatic cancer cells were treated with selenomethionine or RSL3, an inhibitor of glutathione peroxidase 4 (GPx4). Radiation-induced decreases in villi length and increases in 4-HNE immunofluorescence were reversed with P-AscH− in human duodenum. In vivo, radiation-induced decreases in villi length and increased collagen deposition were reversed in P-AscH−-treated jejunal samples. P-AscH− and radiation increased BODIPY oxidation in pancreatic cancer cells but not in non-tumorigenic cells. Selenomethionine increased GPx4 protein and activity in pancreatic cancer and reversed P-AscH−-induced toxicity and lipid peroxidation. RSL3 treatment inhibited GPx4 activity and increased lipid peroxidation. Differences in oxidative stress may play a role in radioprotecting normal cells while radiosensitizing pancreatic cancer cells when treated with P-AscH−. |
| Databáze: | Directory of Open Access Journals |
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