Dataset Information

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^-.

SUBMITTER: Chen GY

PROVIDER: S-EPMC10967795 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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

Chen Gloria Y GY O'Leary Brianne R BR Du Juan J Carroll Rory S RS Steers Garett J GJ Buettner Garry R GR Cullen Joseph J JJ

Antioxidants (Basel, Switzerland) 20240318 3

The toxicity of ionizing radiation limits its effectiveness in the treatment of pancreatic ductal adenocarcinoma. Pharmacologic ascorbate (P-AscH<sup>-</sup>) has been shown to radiosensitize pancreatic cancer cells while simultaneously radioprotecting normal cells. We hypothesize that P-AscH<sup>-</sup> protects the small intestine while radiosensitizing pancreatic cancer cells partially through an oxidative stress mechanism. Duodenal samples from pancreaticoduodenectomy specimens of patients w ...[more]

PMID: 38539894

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Project description:: Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH-, i.e., intravenous infusions of ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations capable of selective cytotoxicity to tumor cells. In doses achievable in humans, P-AscH- decreases the viability and proliferative capacity of pancreatic cancer via a hydrogen peroxide (H2O2)-mediated mechanism. In this study, we demonstrate that P-AscH- radiosensitizes pancreatic cancer cells but inhibits radiation-induced damage to normal cells. Specifically, radiation-induced decreases in clonogenic survival and double-stranded DNA breaks in tumor cells, but not in normal cells, were enhanced by P-AscH-, while radiation-induced intestinal damage, collagen deposition, and oxidative stress were also reduced with P-AscH- in normal tissue. We also report on our first-in-human phase I trial that infused P-AscH- during the radiotherapy "beam on." Specifically, treatment with P-AscH- increased median overall survival compared with our institutional average (21.7 vs. 12.7 months, P = 0.08) and the E4201 trial (21.7 vs. 11.1 months). Progression-free survival in P-AscH--treated subjects was also greater than our institutional average (13.7 vs. 4.6 months, P < 0.05) and the E4201 trial (6.0 months). Results indicated that P-AscH- in combination with gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma is safe and well tolerated with suggestions of efficacy. Because of the potential effect size and minimal toxicity, our findings suggest that investigation of P-AscH- efficacy is warranted in a phase II clinical trial. SIGNIFICANCE: These findings demonstrate that pharmacologic ascorbate enhances pancreatic tumor cell radiation cytotoxicity in addition to offering potential protection from radiation damage in normal surrounding tissue, making it an optimal agent for improving treatment of locally advanced pancreatic adenocarcinoma.

Project description:BackgroundCystinosis is a rare, incurable lysosomal storage disease caused by mutations in the CTNS gene encoding the cystine transporter cystinosin, which leads to lysosomal cystine accumulation in all cells of the body. Patients with cystinosis display signs of podocyte damage characterized by extensive loss of podocytes into the urine at early disease stages, glomerular proteinuria, and the development of focal segmental glomerulosclerosis (FSGS) lesions. Although standard treatment with cysteamine decreases cellular cystine levels, it neither reverses glomerular injury nor prevents the loss of podocytes. Thus, pathogenic mechanisms other than cystine accumulation are involved in podocyte dysfunction in cystinosis.MethodsWe used immortalized patient-derived cystinosis, healthy, and CTNS knockdown podocytes to investigate podocyte dysfunction in cystinosis. The results were validated in our newly in-house developed fluorescent ctns-/-[Tg(fabp10a:gc-EGFP)] zebrafish larvae model. To understand impaired podocyte functionality, static and dynamic permeability assays, tracer-metabolomic analysis, flow cytometry, western blot, and chemical and dynamic redox-sensing fluorescent probes were used.ResultsIn the current study, we discovered that cystinosis podocytes demonstrate increased ferroptotic cell death caused by mitochondrial reactive oxygen species (ROS)-driven membrane lipid peroxidation. Moreover, cystinosis cells present a fragmented mitochondrial network with impaired tricarboxylic acid cycle (TCA) cycle and energy metabolism. Targeting mitochondrial ROS and lipid peroxidation improved podocyte function in vitro and rescued proteinuria in vivo in cystinosis zebrafish larvae.ConclusionsMitochondrial ROS contribute to podocyte injury in cystinosis by driving lipid peroxidation and ferroptosis, which in turn lead to podocyte detachment. This finding adds cystinosis to the list of podocytopathies associated with mitochondrial dysfunction. The identified mechanisms reveal new therapeutic targets and highlight lipid peroxidation as an exploitable vulnerability of cystinosis podocytes.

Dataset Information

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

Publications

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

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