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Published online on September 12, 2005, 10.1073/pnas.0506390102

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*Antioxidants
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*ASCORBIC ACID
*HYDROGEN PEROXIDE
*SODIUM ASCORBATE
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Medical Sciences
Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues

( cell death | ascorbate radical )

Qi Chen *{dagger}, Michael Graham Espey {ddagger}, Murali C. Krishna {ddagger}, James B. Mitchell {ddagger}, Christopher P. Corpe *, Garry R. Buettner {sect}, Emily Shacter {dagger}, and Mark Levine *¶

*Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; {ddagger}Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; {sect}Free Radical and Radiation Biology Program, University of Iowa, Iowa City, IA 52242-1101; and {dagger}Laboratory of Biochemistry, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892

Communicated by J. E. Rall, National Institutes of Health, Bethesda, MD, August 2, 2005 (received for review June 1, 2005)

Human pharmacokinetics data indicate that i.v. ascorbic acid (ascorbate) in pharmacologic concentrations could have an unanticipated role in cancer treatment. Our goals here were to test whether ascorbate killed cancer cells selectively, and if so, to determine mechanisms, using clinically relevant conditions. Cell death in 10 cancer and 4 normal cell types was measured by using 1-h exposures. Normal cells were unaffected by 20 mM ascorbate, whereas 5 cancer lines had EC50 values of <4 mM, a concentration easily achievable i.v. Human lymphoma cells were studied in detail because of their sensitivity to ascorbate (EC50 of 0.5 mM) and suitability for addressing mechanisms. Extracellular but not intracellular ascorbate mediated cell death, which occurred by apoptosis and pyknosis/necrosis. Cell death was independent of metal chelators and absolutely dependent on H2O2 formation. Cell death from H2O2 added to cells was identical to that found when H2O2 was generated by ascorbate treatment. H2O2 generation was dependent on ascorbate concentration, incubation time, and the presence of 0.5-10% serum, and displayed a linear relationship with ascorbate radical formation. Although ascorbate addition to medium generated H2O2, ascorbate addition to blood generated no detectable H2O2 and only trace detectable ascorbate radical. Taken together, these data indicate that ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H2O2, and that blood can be a delivery system of the pro-drug to tissues. These findings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H2O2 may be beneficial.

Author contributions: Q.C., M.G.E., M.C.K., J.B.M., C.P.C., G.R.B., E.S., and M.L. designed research; Q.C., M.G.E., J.B.M., C.P.C., E.S., and M.L. performed research; M.G.E., M.C.K., J.B.M., C.P.C., G.R.B., and E.S. contributed new reagents/analytic tools; Q.C., M.G.E., M.C.K., G.R.B., E.S., and M.L. analyzed data; and Q.C. and M.L. wrote the paper.

To whom correspondence should be addressed at: Molecular and Clinical Nutrition Section, National Institutes of Health, Building 10, Room 4D52, MSC-1372, Bethesda, MD 20892-1372.

Mark Levine, E-mail: markl{at}mail.nih.gov

www.pnas.org/cgi/doi/10.1073/pnas.0506390102
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