Pharmacological ascorbate inhibits pancreatic cancer metastases via a peroxide-mediated mechanism.

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.