Pharmacological Ascorbate Enhances Chemotherapies in Pancreatic Ductal Adenocarcinoma

Abstract

Objectives Pharmacological ascorbate (P-AscH-, high-dose, intravenous vitamin C) has shown promise as an adjuvant therapy for pancreatic ductal adenocarcinoma (PDAC) treatment. The objective of this study was to determine the effects of P-AscH- when combined with PDAC chemotherapies. Methods Clonogenic survival, combination indices, and DNA damage were determined in human PDAC cell lines treated with P-AscH- in combination with 5-fluorouracil, paclitaxel, or FOLFIRINOX (combination of leucovorin, 5-fluorouracil, irinotecan, oxaliplatin). Tumor volume changes, overall survival, blood analysis, and plasma ascorbate concentration were determined in vivo in mice treated with P-AscH- with or without FOLFIRINOX. Results P-AscH- combined with 5-fluorouracil, paclitaxel, or FOLFIRINOX significantly reduced clonogenic survival in vitro. The DNA damage, measured by γH2AX protein expression, was increased after treatment with P-AscH-, FOLFIRINOX, and their combination. In vivo, tumor growth rate was significantly reduced by P-AscH-, FOLFIRINOX, and their combination. Overall survival was significantly increased by the combination of P-AscH- and FOLFIRINOX. Treatment with P-AscH- increased red blood cell and hemoglobin values but had no effect on white blood cell counts. Plasma ascorbate concentrations were significantly elevated in mice treated with P-AscH- with or without FOLFIRINOX. Conclusions The addition of P-AscH- to standard of care chemotherapy has the potential to be an effective adjuvant for PDAC treatment.