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

Sci Rep. 2020 Oct 19;10(1):17649. doi: 10.1038/s41598-020-74806-2.


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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Ascorbic Acid / therapeutic use*
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Female
  • Humans
  • Hydrogen Peroxide / metabolism
  • Liver Neoplasms / secondary
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis / drug therapy
  • Neoplasm Transplantation
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Neoplastic Cells, Circulating / drug effects
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Peroxides / metabolism*


  • Antineoplastic Agents
  • Peroxides
  • Hydrogen Peroxide
  • Ascorbic Acid