{"doi":"10.3390/antiox13030361","title":"Pharmacologic Ascorbate Radiosensitizes Pancreatic Cancer but Radioprotects Normal Tissue: The Role of Oxidative Stress-Induced Lipid Peroxidation","abstract":"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−.","journal":"Antioxidants","year":2024,"id":438034,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":408977,"name":"Brianne R. O’Leary","orcid":"0000-0001-7431-1141","position":1,"is_corresponding":false},{"id":408975,"name":"Juan Du","orcid":"0000-0003-3444-5043","position":2,"is_corresponding":false},{"id":473175,"name":"Rory S. Carroll","orcid":"0000-0001-6622-0231","position":3,"is_corresponding":false},{"id":755173,"name":"Garett J. Steers","orcid":"0000-0001-9210-9828","position":4,"is_corresponding":false},{"id":297603,"name":"Garry R. Buettner","orcid":"0000-0002-5594-1903","position":5,"is_corresponding":false},{"id":401827,"name":"Joseph J. Cullen","orcid":"0000-0002-2222-1328","position":6,"is_corresponding":false},{"id":939721,"name":"Gloria Y. Chen","orcid":null,"position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:00:38.888629Z","pmid":"38539894","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}