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Pharmacological ascorbate (P-AscH − , high-dose, intravenous vitamin C) is cytotoxic to tumor cells in doses achievable in humans. Phase I studies in pancreatic cancer (PDAC) utilizing P-AscH − have demonstrated increases in progression free survival, suggesting a reduction in metastatic disease burden. The purpose of this study was to determine the effects of P-AscH − on metastatic PDAC. Several in vitro and in vivo mechanisms involved in PDAC metastases were investigated following treatment with P-AscH − . Serum from PDAC patients in clinical trials with P-AscH − were tested for the presence and quantity of circulating tumor cell-derived nucleases. P-AscH − inhibited invasion, basement membrane degradation, decreased matrix metalloproteinase expression, as well as clonogenic survival and viability during exposure to fluid shear stress. In vivo , P-AscH − significantly decreased formation of ascites, tumor burden over time, circulating tumor cells, and hepatic metastases. Both in vitro and in vivo findings were reversed with the addition of catalase suggesting that the effect of P-AscH − on metastatic disease is mediated by hydrogen peroxide. Finally, P-AscH − decreased CTC-derived nucleases in subjects with stage IV PDAC in a phase I clinical trial. We conclude that P-AscH − attenuates the metastatic potential of PDAC and may prove to be effective for treating advanced disease.

At pharmacological levels, ascorbate (P-AscH - ) acts as a pro-oxidant by generating H 2 O 2 , depleting ATP in sensitive cells leading to cell death. The aim of this study was to determine the role of ATP production by oxidative phosphorylation or glycolysis in mechanisms of resistance to P-AscH – induced cell death. Pancreatic cancer cells were used to generate ρ 0 cells by mitochondrial overexpression of the Y147A mutant uracil-N-glycosylase or Herpes Simplex Virus protein. The ρ 0 phenotype was confirmed by probing for mitochondrial DNA, mitochondrial DNA-encoded cytochrome c oxidase subunit 2, and monitoring the rate of oxygen consumption. In ρ 0 cells, glycolysis accounted for 100% of ATP production as there was no mitochondrial oxygen consumption. Even though the activities of H 2 O 2 -removing antioxidant enzymes were similar in both the parental and ρ 0 clones, P-AscH - -induced clonogenic cell death in ρ 0 cells showed more resistance than the parental cell line. In addition, P-AscH - induced more DNA damage and more consumption of NAD + and greater decreases in the production of ATP in the parental cell line compared to the ρ 0 cells. Thus, cancer cells that largely use oxidative phosphorylation to generate ATP may be more sensitive to P-AscH - compared with cells that are glycolysis-dependent.

Gastric adenocarcinoma most often presents at an advanced stage and overall five-year survival of ∼30%. Pharmacological ascorbate (high-dose IV ascorbate) has been proposed as a promising nontoxic adjuvant to standard radio-chemotherapies in several cancer types. In the current study, pharmacological ascorbate (0.5–2 mM) caused a dose-dependent decrease (70–85% at 2 mM) in clonogenic survival of gastric adenocarcinoma cells (AGS and MNK-45), but was relatively nontoxic to a small intestinal epithelial nonimmortalized human cell isolate (FHs 74 Int). The addition of pharmacological ascorbate (1 mM) to standard radio-chemotherapies [i.e., 5-FU (5 μM); cisplatin (0.5 μM); irinotecan (2.5 μM); carboplatin (5 μM); paclitaxel (2–4 nM); and X rays (1.8 Gy)] also potentiated gastric cancer clonogenic cell killing [additional decreases were noted with: ascorbate plus 5-FU/radiation (1%); ascorbate plus cisplatin/irinotecan (9–19%); and ascorbate plus paclitaxel/carboplatin (6–7%)]. The gastric cancer cell toxicity and chemosensitization seen with pharmacological ascorbate was dependent on H2O2 and the presence of catalytic metal ions. In addition, pharmacological ascorbate dosing resulted in a concentration-dependent decrease (64% at 20 mM, P ≤ 0.0001) in cancer cell invasion and migration that was inhibited by catalase. Finally, pharmacological ascorbate significantly increased the overall survival of mice with gastric cancer xenografts when used in combination with paclitaxel, carboplatin and radiation (P = 0.019). These results demonstrate that pharmacological ascorbate is selectively cytotoxic to gastric adenocarcinoma cells (relative to normal intestinal epithelial cells) by a mechanism involving H2O2 and redox active metal ions. Furthermore, pharmacological ascorbate significantly enhances gastric cancer xenograft responses to radio-chemotherapy as well as inhibiting tumor cell migration and invasiveness. Overall, these results support the hypothesis that pharmacological ascorbate can be used as an adjuvant with standard-of-care radio-chemotherapies for the treatment of gastric adenocarcinomas.

Cells contain a large number of antioxidants to prevent or repair the damage caused by reactive oxygen species, as well as to regulate redox-sensitive signaling pathways. General protocols are described to measure the antioxidant enzyme activity of superoxide dismutase (SOD), catalase and glutathione peroxidase. The SODs convert superoxide radical into hydrogen peroxide and molecular oxygen, whereas the catalase and peroxidases convert hydrogen peroxide into water. In this way, two toxic species, superoxide radical and hydrogen peroxide, are converted to the harmless product water. Western blots, activity gels and activity assays are various methods used to determine protein and activity in both cells and tissue depending on the amount of protein required for each assay. Other techniques including immunohistochemistry and immunogold can further evaluate the levels of the various antioxidant enzymes in tissues and cells. In general, these assays require 24–48 h to complete.

Pharmacological ascorbate (i.e., intravenous infusions of vitamin C reaching ~ 20 mM in plasma) is under active investigation as an adjuvant to standard of care anti-cancer treatments due to its dual redox roles as an antioxidant in normal tissues and as a prooxidant in malignant tissues. Immune checkpoint inhibitors (ICIs) are highly promising therapies for many cancer patients but face several challenges including low response rates, primary or acquired resistance, and toxicity. Ascorbate modulates both innate and adaptive immune functions and plays a key role in maintaining the balance between pro and anti-inflammatory states. Furthermore, the success of pharmacological ascorbate as a radiosensitizer and a chemosensitizer in pre-clinical studies and early phase clinical trials suggests that it may also enhance the efficacy and expand the benefits of ICIs.

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−.

Pancreatic cancer accounts for nearly one fourth of all new cancers worldwide. Little progress in the development of novel or adjuvant therapies has been made over the past few decades and new approaches to the treatment of pancreatic cancer are desperately needed. Pharmacologic ascorbate (P-AscH−, high-dose, intravenous vitamin C) is being investigated in clinical trials as an adjunct to standard-of-care chemoradiation treatments. In vitro, P-AscH− has been shown to sensitize cancer cells to ionizing radiation in a manner that is dependent on the generation of H2O2 while simultaneously protecting normal tissue from radiation damage. There is renewed interest in Auranofin (Au), an FDA-approved medication utilized in the treatment of rheumatoid arthritis, as an anti-cancer agent. Au inhibits the thioredoxin antioxidant system, thus increasing the overall peroxide burden on cancer cells. In support of current literature demonstrating Au’s effectiveness in breast, colon, lung, and ovarian cancer, we offer additional data that demonstrate the effectiveness of Au alone and in combination with P-AscH− and ionizing radiation in pancreatic cancer treatment. Combining P-AscH− and Au in the treatment of pancreatic cancer may confer multiple mechanisms to increase H2O2-dependent toxicity amongst cancer cells and provide a promising translatable avenue by which to enhance radiation effectiveness and improve patient outcomes.

Vitamin C also delayed the impact of adverse events and improved quality of life. Improvements in survival, quality of life Results showed longer PFS (median, 6.2 months vs. 3.9 months; HR = 0.43; 90% CI, 0.2-0.92) and OS (median, 16 months vs. 8.3 months; HR = 0.46; 90% CI, 0.23-0.92) with the addition of vitamin C. Historically, patients who received the control regimen achieved median OS of 8.5 months. Researchers conducted an exploratory analysis on quality of life.

Obesity is a risk factor for many comorbid conditions that increase the cost of health care. We sought to examine the effect of obesity on surgical complications and cost in a group of patients undergoing intestinal surgery. Using the Veterans Affairs Surgical Quality Improvement Program (VASQIP), which includes clinical data abstracted from medical records for Veterans Affairs (VA) surgical patients, and the VA Decision Support System, which provides the costs of individual patient encounters on the basis of relative values assigned to intermediate products, we examined surgical complications and costs of care in 4,881 patients undergoing intestinal surgery in 2006. Patients were classified into 4 groups based on body mass index (BMI): malnourished (<18), normal weight (18–30), obesity class I to II (30–40), and obesity class III (>40). Patient endpoints included the occurrence of any complication and surgical costs incurred within 30 days of surgery. Endpoints were compared across the 4 BMI categories in unadjusted analyses and risk-adjusted analyses and hospital-level variation using multivariable models. After controlling for patient risk factors and hospital-level variation, patients in obesity class I to II were 1.21 times more likely to have any complication and patients in obesity class III were 1.41 times more likely to have any complication when compared with normal-weight patients. Similarly, patients in obesity class I to II were 1.44 times more likely to develop a wound complication compared with normal-weight patients, and patients in class III were 1.84 times more likely to develop a wound complication and 1.55 times more likely to develop a respiratory complication compared with normal-weight patients. In contrast, costs were greatest for malnourished patients at $45,000 compared with normal-weight patients at $37,000. However, after controlling for patient risk factors and variation in costs attributable to the admitting hospital, there were no significant cost differences between the 4 BMI categories. Obesity leads to increased wound and respiratory complications in intestinal surgery. Nevertheless, obesity alone is not an independent risk factor for increased costs in intestinal surgery.

The incidence of pancreatic cancer is increasing as the population ages but treatment advancements continue to lag far behind. The majority of pancreatic cancer patients have a K-ras oncogene mutation causing a shift in the redox state of the cell, favoring malignant proliferation. This mutation is believed to lead to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and superoxide overproduction, generating tumorigenic behavior. Superoxide dismutases (SODs) have been studied for their ability to manage the oxidative state of the cell by dismuting superoxide and inhibiting signals for pancreatic cancer growth. In particular, manganese superoxide dismutase has clearly shown importance in cell cycle regulation and has been found to be abnormally low in pancreatic cancer cells as well as the surrounding stromal tissue. Likewise, extracellular superoxide dismutase expression seems to favor suppression of pancreatic cancer growth. With an increased understanding of the redox behavior of pancreatic cancer and key regulators, new treatments are being developed with specific targets in mind. This review summarizes what is known about superoxide dismutases in pancreatic cancer and the most current treatment strategies to be advanced from this knowledge.