Abstract
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.
Highlights
Pharmacological ascorbate (P-AscH−, high-dose, intravenous vitamin C) is cytotoxic to tumor cells in doses achievable in humans
Our current study demonstrates that P-AscH− inhibits invasion and degradation of the basement membrane as well as matrix metalloproteinases associated with metastatic disease progression in metabolically active Pancreatic ductal adenocarcinoma (PDAC) cells in vitro
To determine the ability for cells to invade through the extracellular matrix (ECM) an invasion assay was performed
Summary
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. 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. Two phase I studies (NCT 01049880 & NCT 01852890)[6,7] at The University of Iowa demonstrated that patients receiving P-AscH− had increased progression free survival compared to historical controls in both studies, suggesting that P-AscH− can reduce metastatic disease burden in PDAC
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