Journal article
Pharmacologic Ascorbate Radiosensitizes Pancreatic Cancer but Radioprotects Normal Tissue: The Role of Oxidative Stress-Induced Lipid Peroxidation
Antioxidants, Vol.13(3), 361
03/18/2024
DOI: 10.3390/antiox13030361
PMCID: PMC10967795
PMID: 38539894
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
.
Details
- Title: Subtitle
- Pharmacologic Ascorbate Radiosensitizes Pancreatic Cancer but Radioprotects Normal Tissue: The Role of Oxidative Stress-Induced Lipid Peroxidation
- Creators
- Gloria Y Chen - University of IowaBrianne R O'Leary - University of IowaJuan Du - University of IowaRory S Carroll - University of IowaGarett J Steers - University of IowaGarry R Buettner - University of IowaJoseph J Cullen - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Antioxidants, Vol.13(3), 361
- DOI
- 10.3390/antiox13030361
- PMID
- 38539894
- PMCID
- PMC10967795
- ISSN
- 2076-3921
- eISSN
- 2076-3921
- Grant note
- PO1 217797 / NIH HHS T32 CA78586 / NIH HHS
- Language
- English
- Date published
- 03/18/2024
- Academic Unit
- Surgery; Radiation Oncology
- Record Identifier
- 9984577110902771
Metrics
5 Record Views