title: Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice.
abstract: 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.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, and Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Michael Graham
authors.initials: MG
authors.lastname: Espey
authors.forename: Andrew Y
authors.initials: AY
authors.lastname: Sun
authors.forename: Chaya
authors.initials: C
authors.lastname: Pooput
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Kirk
authors.forename: Murali C
authors.initials: MC
authors.lastname: Krishna
authors.forename: Deena Beneda
authors.initials: DB
authors.lastname: Khosh
authors.forename: Jeanne
authors.initials: J
authors.lastname: Drisko
authors.forename: Mark
authors.initials: M
authors.lastname: Levine
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000975:Antioxidants / Q000008:administration & dosage / Q000493:pharmacokinetics; D001205:Ascorbic Acid / Q000008:administration & dosage* / Q000378:metabolism; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007262:Infusions, Intravenous; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016877:Oxidants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D016877:Oxidants; D011355:Prodrugs; D006861:Hydrogen Peroxide; D001205:Ascorbic Acid