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Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice
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Edited by Bruce N. Ames, Children's Hospital Oakland Research Institute, Oakland, CA, and approved June 6, 2008
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↵†Q.C. and M.G.E. contributed equally to this work. (received for review May 1, 2008)
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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.
Footnotes
- ↵‡To whom correspondence may be addressed at: Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, 10/4D52, 9000 Rockville Pike, National Institutes of Health, Bethesda, MD 20892. E-mail: sp{at}nih.gov or mark.levine{at}nih.gov
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Author contributions: Q.C., M.G.E., and M.L. designed research; Q.C., M.G.E., A.Y.S., D.B.K., and J.D. performed research; C.P., K.L.K., and M.C.K. contributed new reagents/analytical tools; Q.C., M.G.E., C.P., K.L.K., M.C.K., J.D., and M.L. analyzed data; and M.G.E. and M.L. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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See Commentary on page 11037.
- Received May 1, 2008.
- © 2008 by The National Academy of Sciences of the USA