Treatment of Pancreatic Cancer with Pharmacological Ascorbate

Abstract

The prognosis for patients diagnosed with pancreatic cancer remains dismal, with less than 3% survival at 5 years. Recent studies have demonstrated that high-dose, intravenous pharmacological ascorbate (ascorbic acid, vitamin C) induces cytotoxicity and oxidative stress selectively in pancreatic cancer cells vs. normal cells, suggesting a promising new role of ascorbate as a therapeutic agent. At physiologic concentrations, ascorbate functions as a reducing agent and antioxidant. However, when pharmacological ascorbate is given intravenously, it is possible to achieve millimolar plasma concentration. At these pharmacological levels, and in the presence of catalytic metal ions, ascorbate can induce oxidative stress through the generation of hydrogen peroxide (H2O2). Recent in vitro and in vivo studies have demonstrated ascorbate oxidation occurs extracellularly, generating H2O2 flux into cells resulting in oxidative stress. Pharmacologic ascorbate also inhibits the growth of pancreatic tumor xenografts and displays synergistic cytotoxic effects when combined with gemcitabine in pancreatic cancer. Phase I trials of pharmacological ascorbate in pancreatic cancer patients have demonstrated safety and potential efficacy. In this chapter, we will review the mechanism of ascorbate-induced cytotoxicity, examine the use of pharmacological ascorbate in treatment and assess the current data supporting its potential as an adjuvant in pancreatic cancer.

Conflict of interest statement

CONFLICT OF INTEREST

The author(s) confirm that this article content has no conflict of interest.

Figures

Fig. 1

Ascorbate oxidation results in a 2-electron reduction of dioxygen forming H2O2. G-6-PD = glucose-6-phosphate dehydrogenase; GPx = glutathione peroxidase; GR = glutathione disulfide reductase; Grx = glutaredoxin; GSH = glutathione; GSSG = glutathione disulfide; Trx = thioredoxin.

Fig. 2

Antioxidant enzyme schematic. GSH = glutathione; GSSG = glutathione disulfide; GR = glutathione disulfide reductase; G-6-PD = glucose-6-phosphate dehydrogenase; ᵞGCS = gamma-glutamylcysteine synthetase; GPx = glutathione peroxidase; GS = glutathione synthetase. Inhibitors of the pathway are: 3-AT= 3-amino-1,2,4-triazole; BCNU = 1,3 bis (2-chloroethyl)-1-nitrosurea; BSO = buthionine sulfoximine; 2DG = 2-deoxy-D-glucose.

Fig. 3

Progression free and overall survival. This phase I trial was designed to determine the effect of escalating doses of ascorbate when combined with gemcitabine in stage IV pancreatic cancer patients. The trial utilized a modified Burris regimen, administering gemcitabine for 3 weeks for each cycle of therapy along with ascorbate given twice weekly for every week. Historic median survival for gemcitabine-treated patients alone is 5.65 months. The mean survival in our study currently stands at 15 months.