Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner GR, Shacter E, Levine M.
Source
Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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Pharmacologic Ascorbic Acid (Vitamin C) Concentrations Selectively Kill Cancer Cells:
Action as a Pro-Drug to Deliver H2O2 Hydrogen Peroxide to Tissues
Abstract
Human pharmacokinetics data indicate that i.v. ascorbic acid (vitamin C) in pharmacologic concentrations could have an unanticipated role in cancer treatment.
Our goals here were to test whether i.v. ascorbic acid (vitamin C) 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 i.v. ascorbic acid (vitamin C), whereas 5 cancer lines had EC(50) values of <4 mM, a concentration easily achievable.
i.v. Human lymphoma cells were studied in detail because of their sensitivity to ascorbate (EC(50) of 0.5 mM) and suitability for addressing mechanisms.
Extracellular but not intracellular i.v. ascorbic acid (vitamin C) 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 i.v. ascorbic acid (vitamin C) treatment.
H2O2 generation was dependent on i.v. ascorbic acid (vitamin C) 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, i.v. ascorbic acid (vitamin C) ascorbate addition to blood generated no detectable H2O2 and only trace detectable ascorbate radical.
Taken together, these data indicate that (vitamin C) 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 (vitamin C) in cancer treatment, and have unexpected implications for treatment of infections where H2O2 may be beneficial.
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Figure 1.
Effects of pharmacologic ascorbic acid concentrations on cancer and normal cells.
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Figure 2.
Effects of ascorbic acid on human Burkitt's lymphoma cells.
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Figure 3.
Extracellular ascorbate kills human Burkitt's lymphoma cells by generating H2O2.
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Figure 4.
Enhancing factors for ascorbate-mediated H2O2 generation in cell culture medium.
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Figure 5.
Human blood inhibits H2O2 and ascorbate radical generation from ascorbate.
