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

1.   Qi Chen <http://www.pnas.org/search?author1=Qi+Chen&sortspec=date&submit=Submit> * <http://www.pnas.org/content/105/32/11105#aff-1> ,† <http://www.pnas.org/content/105/32/11105#fn-3> ,

2.   Michael Graham Espey <http://www.pnas.org/search?author1=Michael+Graham+Espey&sortspec=date&submit=Submit> * <http://www.pnas.org/content/105/32/11105#aff-1> ,† <http://www.pnas.org/content/105/32/11105#fn-3> ,‡ <http://www.pnas.org/content/105/32/11105#corresp-1> ,

3.   Andrew Y. Sun <http://www.pnas.org/search?author1=Andrew+Y.+Sun&sortspec=date&submit=Submit> * <http://www.pnas.org/content/105/32/11105#aff-1> ,

4.   Chaya Pooput <http://www.pnas.org/search?author1=Chaya+Pooput&sortspec=date&submit=Submit> § <http://www.pnas.org/content/105/32/11105#aff-2> ,

5.   Kenneth L. Kirk <http://www.pnas.org/search?author1=Kenneth+L.+Kirk&sortspec=date&submit=Submit> § <http://www.pnas.org/content/105/32/11105#aff-2> ,

6.   Murali C. Krishna <http://www.pnas.org/search?author1=Murali+C.+Krishna&sortspec=date&submit=Submit> ¶ <http://www.pnas.org/content/105/32/11105#aff-3> ,

7.   Deena Beneda Khosh <http://www.pnas.org/search?author1=Deena+Beneda+Khosh&sortspec=date&submit=Submit> ‖ <http://www.pnas.org/content/105/32/11105#aff-4> ,

8.   Jeanne Drisko <http://www.pnas.org/search?author1=Jeanne+Drisko&sortspec=date&submit=Submit> ‖ <http://www.pnas.org/content/105/32/11105#aff-4> , and

9.   Mark Levine <http://www.pnas.org/search?author1=Mark+Levine&sortspec=date&submit=Submit> * <http://www.pnas.org/content/105/32/11105#aff-1> ,‡ <http://www.pnas.org/content/105/32/11105#corresp-1> 

+ <http://www.pnas.org/content/105/32/11105> Author Affiliations

1.    *Molecular and Clinical Nutrition Section and

2.    §Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, and

3.    ¶Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and

4.    ‖Program in Integrative Medicine, University of Kansas Medical Center, Kansas City, KS 66160

1.     Edited by Bruce N. Ames, Children's Hospital Oakland Research Institute, Oakland, CA, and approved June 6, 2008

2.     ↵ <http://www.pnas.org/content/105/32/11105#xref-fn-3-1> †Q.C. and M.G.E. contributed equally to this work. (received for review May 1, 2008)

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.

cancer <http://www.pnas.org/search?fulltext=cancer&sortspec=date&submit=Submit> 

hydrogen peroxide <http://www.pnas.org/search?fulltext=hydrogen+peroxide&sortspec=date&submit=Submit> 

oxidation <http://www.pnas.org/search?fulltext=oxidation&sortspec=date&submit=Submit> 

free radical <http://www.pnas.org/search?fulltext=free+radical&sortspec=date&submit=Submit> 

vitamin C <http://www.pnas.org/search?fulltext=vitamin+C&sortspec=date&submit=Submit> 

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@nih.gov <mailto:sp@nih.gov&gt;  or mark.levine@nih.gov <mailto:mark.levine@nih.gov&gt; 

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.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

See Commentary on page 11037 <http://www.pnas.org/lookup/volpage/105/11037> .

© 2008 by The National Academy of Sciences of the USA

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