Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-08, Vol.105 (32), p.11105-11109
• Main Authors: Chen, Qi, Espey, Michael Graham, Sun, Andrew Y, Pooput, Chaya, Kirk, Kenneth L, Krishna, Murali C, Khosh, Deena Beneda, Drisko, Jeanne, Levine, Mark
• Format: Article
• Language: English
• Subjects: Animals; anticarcinogenic activity; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antioxidants; Antioxidants - administration & dosage; Antioxidants - pharmacokinetics; ascorbate radical; ascorbic acid; Ascorbic Acid - administration & dosage; Ascorbic Acid - metabolism; Biological Sciences; Blood; Blood plasma; Cancer; Cell lines; Cells; cytotoxicity; Dosage; Drug dosages; Extracellular fluid; Female; free radicals; Glioblastoma; Humans; hydrogen peroxide; Hydrogen Peroxide - metabolism; Infusions, Intravenous; intraperitoneal injection; Mice; Mice, Nude; neoplasms; Neoplasms - drug therapy; Neoplasms - metabolism; ovarian neoplasms; Oxidants - administration & dosage; Oxidants - pharmacokinetics; pancreas; Pharmacology; Prodrugs - administration & dosage; Prodrugs - pharmacokinetics; Rodents; Studies; Tumors; Vitamin C; Xenograft Model Antitumor Assays; xenotransplantation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0804226105

Ascorbic acid is an essential nutrient commonly regarded as an antioxidant. In this study, we showed that ascorbate at pharmacologic concentrations was a prooxidant, generating hydrogen-peroxide-dependent cytotoxicity toward a variety of cancer cells in vitro without adversely affecting normal cells. To test this action in vivo, normal oral tight control was bypassed by parenteral ascorbate administration. Real-time microdialysis sampling in mice bearing glioblastoma xenografts showed that a single pharmacologic dose of ascorbate produced sustained ascorbate radical and hydrogen peroxide formation selectively within interstitial fluids of tumors but not in blood. Moreover, a regimen of daily pharmacologic ascorbate treatment significantly decreased growth rates of ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P < 0.001) tumors established in mice. Similar pharmacologic concentrations were readily achieved in humans given ascorbate intravenously. These data suggest that ascorbate as a prodrug may have benefits in cancers with poor prognosis and limited therapeutic options.