Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer

Abstract

Conventional treatment approaches have had little impact on the course of pancreatic cancer, which has the highest fatality rate among cancers. Gemcitabine, the primary therapeutic agent for pancreatic carcinoma, produces minimal survival benefit as a single agent. Therefore, numerous efforts have focused on gemcitabine combination treatments. Using a ratio design, this study established that combining pharmacologically achievable concentrations of ascorbate with gemcitabine resulted in a synergistic cytotoxic response in eight pancreatic tumor cell lines. Sensitization was evident regardless of inherent gemcitabine resistance and epithelial–mesenchymal phenotype. Our analysis suggested that the promiscuous oxidative actions of H2O2 derived from pharmacologic ascorbate can culminate in synergism independent of the cancer cell's underlying phenotype and resistance to gemcitabine monotherapy. Gemcitabine–ascorbate combinations administered to mice bearing pancreatic tumor xenografts consistently enhanced inhibition of growth compared to gemcitabine alone, produced 50% growth inhibition in a tumor type not responsive to gemcitabine, and demonstrated a gemcitabine dose-sparing effect. These data support the testing of pharmacologic ascorbate in adjunctive treatments for cancers prone to high failure rates with conventional therapeutic regimens, such as pancreatic cancer.

Proposed Insights in the Pharmaco-Dynamic Theory of Ascorbate Pro-Oxidant Activity

“…6). This point is supported by several in vitro and in vivo data suggesting that vitamin C may overcome chemoresistance and improve chemosensitivity and cell fragility (Espey et al, 2011;Grad et al, 2001;Kurbacher et al, 1996;Song et al, 1995;Reddy et al, 2001). Besides, the presence of metal catalyst like copper ions should induce lipid peroxidation according to the pro-drug theory, but in our study we demonstrate that the highest levels of MDA are obtained with ascorbate alone without copper neither in the Udenfriend system.…”

Molecular mechanisms of pharmacological doses of ascorbate on cancer cells

“…administration of ascorbate significantly decreased the tumor burden in three different mouse models (ovarian cancer, pancreas cancer, glioblastoma) and formation of metastases, as observed in 30 % of the untreated glioblastoma control group was not observed at all in the ascorbate-treated glioblastoma group [8]. Furthermore, ascorbate had a synergistic effect in combination with gemcitabine in terms of tumor growth reduction in a pancreatic cancer mouse model [23].…”

Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics

“…Pharmacologic ascorbate enhanced gemcitabine activity in a study of eight pancreatic cancer cell lines (24). In all cell lines, gemcitabine combined with ascorbate was more effective than gemcitabine alone.…”

“…**indicates a p value < 0.002 using a paired two-tailed t-test. Reprinted by permission from Espey et al (24). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars 2150 PARROW ET AL.…”