{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T07:51:31Z","timestamp":1779177091195,"version":"3.51.4"},"reference-count":45,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T00:00:00Z","timestamp":1710720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P01 217797"],"award-info":[{"award-number":["P01 217797"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["T32 CA78586"],"award-info":[{"award-number":["T32 CA78586"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["1P30 CA086862-23"],"award-info":[{"award-number":["1P30 CA086862-23"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011343","name":"Holden Comprehensive Cancer Center","doi-asserted-by":"publisher","award":["P01 217797"],"award-info":[{"award-number":["P01 217797"]}],"id":[{"id":"10.13039\/100011343","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011343","name":"Holden Comprehensive Cancer Center","doi-asserted-by":"publisher","award":["T32 CA78586"],"award-info":[{"award-number":["T32 CA78586"]}],"id":[{"id":"10.13039\/100011343","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011343","name":"Holden Comprehensive Cancer Center","doi-asserted-by":"publisher","award":["1P30 CA086862-23"],"award-info":[{"award-number":["1P30 CA086862-23"]}],"id":[{"id":"10.13039\/100011343","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>The toxicity of ionizing radiation limits its effectiveness in the treatment of pancreatic ductal adenocarcinoma. Pharmacologic ascorbate (P-AscH\u2212) has been shown to radiosensitize pancreatic cancer cells while simultaneously radioprotecting normal cells. We hypothesize that P-AscH\u2212 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 \u00b1 P-AscH\u2212 and mouse tumor and jejunal samples treated with radiation \u00b1 P-AscH\u2212 were evaluated. Pancreatic cancer and non-tumorigenic cells were treated with radiation \u00b1 P-AscH\u2212 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\u2212 in human duodenum. In vivo, radiation-induced decreases in villi length and increased collagen deposition were reversed in P-AscH\u2212-treated jejunal samples. P-AscH\u2212 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\u2212-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\u2212.<\/jats:p>","DOI":"10.3390\/antiox13030361","type":"journal-article","created":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T05:14:07Z","timestamp":1710738847000},"page":"361","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Pharmacologic Ascorbate Radiosensitizes Pancreatic Cancer but Radioprotects Normal Tissue: The Role of Oxidative Stress-Induced Lipid Peroxidation"],"prefix":"10.3390","volume":"13","author":[{"given":"Gloria Y.","family":"Chen","sequence":"first","affiliation":[{"name":"Departments of Surgery, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7431-1141","authenticated-orcid":false,"given":"Brianne R.","family":"O\u2019Leary","sequence":"additional","affiliation":[{"name":"Departments of Surgery, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"},{"name":"Free Radical and Radiation Biology Division, Department of Radiation Oncology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Du","sequence":"additional","affiliation":[{"name":"Departments of Surgery, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"},{"name":"Free Radical and Radiation Biology Division, Department of Radiation Oncology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rory S.","family":"Carroll","sequence":"additional","affiliation":[{"name":"Departments of Surgery, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9210-9828","authenticated-orcid":false,"given":"Garett J.","family":"Steers","sequence":"additional","affiliation":[{"name":"Departments of Surgery, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5594-1903","authenticated-orcid":false,"given":"Garry R.","family":"Buettner","sequence":"additional","affiliation":[{"name":"Free Radical and Radiation Biology Division, Department of Radiation Oncology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2222-1328","authenticated-orcid":false,"given":"Joseph J.","family":"Cullen","sequence":"additional","affiliation":[{"name":"Departments of Surgery, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"},{"name":"Free Radical and Radiation Biology Division, Department of Radiation Oncology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,18]]},"reference":[{"key":"ref_1","unstructured":"National Cancer Institute (2023, February 01). Cancer Stat Facts: Pancreatic Cancer, Available online: https:\/\/seer.cancer.gov\/statfacts\/html\/pancreas.html."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4298","DOI":"10.3748\/wjg.v27.i27.4298","article-title":"Pancreatic cancer: A review of epidemiology, trend, and risk factors","volume":"27","author":"Hu","year":"2021","journal-title":"World J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1146\/annurev-med-081313-121208","article-title":"The DNA damage response: Implications for tumor responses to radiation and chemotherapy","volume":"66","author":"Goldstein","year":"2015","journal-title":"Annu. Rev. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/0167-8140(90)90123-E","article-title":"DNA damage and repair following treatment with ionizing radiation","volume":"19","author":"Powell","year":"1990","journal-title":"Radiother. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1269\/jrr.07130","article-title":"Current topics in DNA double-strand break repair","volume":"49","author":"Kobayashi","year":"2008","journal-title":"J. Radiat. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.4251\/wjgo.v13.i12.2064","article-title":"Current status of non-surgical treatment of locally advanced pancreatic cancer","volume":"13","author":"Spiliopoulos","year":"2021","journal-title":"World J. Gastrointest. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.suc.2017.09.008","article-title":"The Evolving Role of Radiation in Pancreatic Cancer","volume":"98","author":"Landau","year":"2018","journal-title":"Surg. Clin. N. Am."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13014-022-01988-6","article-title":"MR-guided adaptive stereotactic body radiotherapy (SBRT) of primary tumor for pain control in metastatic pancreatic ductal adenocarcinoma (mPDAC): An open randomized, multicentric, parallel group clinical trial (MASPAC)","volume":"17","author":"Pavic","year":"2022","journal-title":"Radiat. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"100763","DOI":"10.1016\/j.adro.2021.100763","article-title":"Stereotactic Versus Conventional Radiation Therapy for Patients With Pancreatic Cancer in the Modern Era","volume":"6","author":"Thunshelle","year":"2021","journal-title":"Adv. Radiat. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3704","DOI":"10.1073\/pnas.93.8.3704","article-title":"Vitamin C pharmacokinetics in healthy volunteers: Evidence for a recommended dietary allowance","volume":"93","author":"Levine","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1007\/s00280-013-2070-8","article-title":"Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): Results from a phase I clinical trial","volume":"71","author":"Welsh","year":"2013","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1158\/1078-0432.CCR-09-1713","article-title":"Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer","volume":"16","author":"Du","year":"2010","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.freeradbiomed.2015.02.018","article-title":"Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer","volume":"83","author":"Cieslak","year":"2015","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5232","DOI":"10.1158\/0008-5472.CAN-13-0470","article-title":"Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation","volume":"73","author":"Rawal","year":"2013","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1016\/j.freeradbiomed.2011.03.007","article-title":"Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer","volume":"50","author":"Espey","year":"2011","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1097\/MPA.0000000000002086","article-title":"Pharmacological Ascorbate Enhances Chemotherapies in Pancreatic Ductal Adenocarcinoma","volume":"51","author":"Ruppenkamp","year":"2022","journal-title":"Pancreas"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6838","DOI":"10.1158\/0008-5472.CAN-18-1680","article-title":"Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer","volume":"78","author":"Alexander","year":"2018","journal-title":"Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1158\/0008-5472.CAN-14-1707","article-title":"Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer","volume":"75","author":"Du","year":"2015","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4105","DOI":"10.1200\/JCO.2011.34.8904","article-title":"Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: An Eastern Cooperative Oncology Group trial","volume":"29","author":"Loehrer","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Roy, I., Zimmerman, N.P., Mackinnon, A.C., Tsai, S., Evans, D.B., and Dwinell, M.B. (2014). CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090400"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1038\/nprot.2009.171","article-title":"Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice","volume":"4","author":"Kim","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1667\/RR15189.1","article-title":"Enhanced Pharmacological Ascorbate Oxidation Radiosensitizes Pancreatic Cancer","volume":"191","author":"Alexander","year":"2019","journal-title":"Radiat. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1158\/0008-5472.CAN-07-5714","article-title":"Cancer-associated stromal fibroblasts promote pancreatic tumor progression","volume":"68","author":"Hwang","year":"2008","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100077","DOI":"10.1016\/j.arres.2023.100077","article-title":"Stability of aqueous solutions of ascorbate for basic research and for intravenous administration","volume":"9","author":"Wagner","year":"2023","journal-title":"Adv. Redox Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Doskey, C.M., van \u2018t Erve, T.J., Wagner, B.A., and Buettner, G.R. (2015). Moles of a Substance per Cell Is a Highly Informative Dosing Metric in Cell Culture. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132572"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3905","DOI":"10.1158\/1078-0432.CCR-12-0287","article-title":"Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts","volume":"19","author":"Allen","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"360438","DOI":"10.1155\/2014\/360438","article-title":"Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal","volume":"2014","author":"Ayala","year":"2014","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0021-9258(19)50881-X","article-title":"A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase","volume":"195","author":"Beers","year":"1952","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0076-6879(84)05016-3","article-title":"Catalase in vitro","volume":"105","author":"Aebi","year":"1984","journal-title":"Methods Enzymol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Stolwijk, J.M., Falls-Hubert, K.C., Searby, C.C., Wagner, B.A., and Buettner, G.R. (2020). Simultaneous detection of the enzyme activities of GPx1 and GPx4 guide optimization of selenium in cell biological experiments. Redox Biol., 32.","DOI":"10.1016\/j.redox.2020.101518"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3159","DOI":"10.1038\/nprot.2006.378","article-title":"Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method","volume":"1","author":"Rahman","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.redox.2016.10.010","article-title":"Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological ascorbate in cancer therapy","volume":"10","author":"Doskey","year":"2016","journal-title":"Redox Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.cell.2013.12.010","article-title":"Regulation of ferroptotic cancer cell death by GPX4","volume":"156","author":"Yang","year":"2014","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5593","DOI":"10.1038\/onc.2017.146","article-title":"ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner","volume":"36","author":"Chen","year":"2017","journal-title":"Oncogene"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.bbrc.2019.08.096","article-title":"RSL3 induced autophagic death in glioma cells via causing glycolysis dysfunction","volume":"518","author":"Wang","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.semradonc.2018.10.006","article-title":"Pharmacological Ascorbate as a Means of Sensitizing Cancer Cells to Radio-Chemotherapy While Protecting Normal Tissue","volume":"29","author":"Schoenfeld","year":"2019","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"17649","DOI":"10.1038\/s41598-020-74806-2","article-title":"Pharmacological ascorbate inhibits pancreatic cancer metastases via a peroxide-mediated mechanism","volume":"10","author":"Alexander","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Du, J., Carroll, R.S., Steers, G.J., Wagner, B.A., O\u2019Leary, B.R., Jensen, C.S., Buettner, G.R., and Cullen, J.J. (2021). Catalase Modulates the Radio-Sensitization of Pancreatic Cancer Cells by Pharmacological Ascorbate. Antioxidants, 10.","DOI":"10.3390\/antiox10040614"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/bs.mcb.2022.05.003","article-title":"Assessment of lipid peroxidation in irradiated cells","volume":"172","author":"Mao","year":"2022","journal-title":"Methods Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/0014-5793(73)80755-0","article-title":"Glutathione peroxidase: A selenoenzyme","volume":"32","author":"Flohe","year":"1973","journal-title":"FEBS Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/0304-4165(85)90182-5","article-title":"The selenoenzyme phospholipid hydroperoxide glutathione peroxidase","volume":"839","author":"Ursini","year":"1985","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Stolwijk, J.M., Garje, R., Sieren, J.C., Buettner, G.R., and Zakharia, Y. (2020). Understanding the Redox Biology of Selenium in the Search of Targeted Cancer Therapies. Antioxidants, 9.","DOI":"10.3390\/antiox9050420"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.3389\/fphar.2018.01371","article-title":"RSL3 Drives Ferroptosis Through GPX4 Inactivation and ROS Production in Colorectal Cancer","volume":"9","author":"Sui","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_45","first-page":"143","article-title":"Lipid Peroxidation-Dependent Cell Death Regulated by GPx4 and Ferroptosis","volume":"403","author":"Imai","year":"2017","journal-title":"Curr. Top Microbiol. Immunol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/3\/361\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:15:14Z","timestamp":1760105714000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/3\/361"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,18]]},"references-count":45,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["antiox13030361"],"URL":"https:\/\/doi.org\/10.3390\/antiox13030361","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,18]]}}}