Pharmacological ascorbate inhibits pancreatic cancer metastases via a peroxide-mediated mechanism
| Autor: | Brianne R. O'Leary, Juan Du, Devon L. Moose, Matthew S. Alexander, Joseph J. Cullen, Michael D. Henry |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
lcsh:Medicine
Mice Nude Antineoplastic Agents Ascorbic Acid Matrix metalloproteinase Article Mice Circulating tumor cell Medical research In vivo Pancreatic cancer Cell Line Tumor medicine Cytotoxic T cell Animals Humans Progression-free survival Neoplasm Metastasis lcsh:Science Cancer Multidisciplinary business.industry lcsh:R Liver Neoplasms Hydrogen Peroxide Neoplasms Experimental medicine.disease Neoplastic Cells Circulating In vitro Peroxides Pancreatic Neoplasms Oncology Cancer research Experimental pathology lcsh:Q Female business Neoplasm Transplantation Carcinoma Pancreatic Ductal |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-13 (2020) |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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