Pharmacologic Ascorbate Radiosensitizes Pancreatic Cancer but Radioprotects Normal Tissue: The Role of Oxidative Stress-Induced Lipid Peroxidation

• Main Authors: Gloria Y. Chen (Author), Brianne R. O'Leary (Author), Juan Du (Author), Rory S. Carroll (Author), Garett J. Steers (Author), Garry R. Buettner (Author), Joseph J. Cullen (Author)
• Format: Book
• Published: MDPI AG, 2024-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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⁻.

Item Description

10.3390/antiox13030361
2076-3921