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Cited by 1,075Vitamin C and Antioxidants ResearchCancer and biochemical researchRedox biology and oxidative stress

Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues

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Chen, Qi, Espey, Michael Graham, Krishna, Murali C., Mitchell, James B., Corpe, Christopher P., Buettner, Garry R., Shacter, Emily, Levine, Mark·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0506390102PMC PMC1224653
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Abstract

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 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 ascorbate mediated cell death, which occurred by apoptosis and pyknosis/necrosis. Cell death was independent of metal chelators and absolutely dependent on H(2)O(2) formation. Cell death from H(2)O(2) added to cells was identical to that found when H(2)O(2) was generated by ascorbate treatment. H(2)O(2) 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 H(2)O(2), ascorbate addition to blood generated no detectable H(2)O(2) 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 H(2)O(2), 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 H(2)O(2) may be beneficial.

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Crossref · 10.1073/pnas.0506390102

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  • Vitamin C given intravenously increases the production of hydrogen peroxide dose-dependently in extracellular fluid but not in blood.

    “It was shown that vitamin C given intravenously increases the production of hydrogen peroxide dose-dependently in extracellular fluid but not in blood.”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [180]

    The Results report that H2O2 formation increased as a function of ascorbate concentration in medium, used as a surrogate for extracellular fluid, while H2O2 was not detected in whole blood. The Discussion says intravenous ascorbate *may* deliver H2O2 to the extracellular milieu; the paper did not directly show this dose-dependent effect after intravenous administration. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The viability of healthy cells is not affected by vitamin C even at 20 mM concentration.

    “The viability of healthy cells is not affected by vitamin C even at 20 mM concentration, i.e., at common concentrations achieved by administration of high doses of vitamin C.”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [180]

    The Results state that all four tested normal cell types were insensitive to 20 mM ascorbate after a 1-hour exposure. However, the same section gives 0.3–15 mM as the achievable plasma range with intravenous administration; it does not support describing 20 mM as a commonly achieved concentration. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Tumor cells are much more, although variably, sensitive to vitamin C, with EC50 of vitamin C below 20 mM in all tested cases of human and mouse cancer cells lines.

    “Tumor cells are much more, although variably, sensitive to vitamin C, with EC50 of vitamin C below 20 mM in all tested cases of human and mouse cancer cells lines [180,181].”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [180]

    The Results report that five of nine cancer cell lines had EC50 values below 5 mM and that all tested normal cells were insensitive to 20 mM ascorbate. This supports selective, variable sensitivity, but the paper does not establish an EC50 below 20 mM for every tested cancer cell line. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Many cell-culture experiments show that pharmacological ascorbate makes extracellular H2O2 that can directly destroy cancer cells.

    “Numerous in vitro cell culture studies have shown that pharmacological ascorbate produces extracellular H2O2, which can directly kill cancer cells26–28.”

    From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [26]

  • Native vitamin C is toxic in culture through the formation of extracellular H2O2, potentially masking its more biologically relevant epigenetic effects.

    “Multiple lines of evidence have suggested that vitamin C, in its native form, is toxic in culture through the formation of extracellular H2O2(refs 16, 17) potentially masking its more biologically relevant epigenetic effects.”

    From Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia (2018) · cites this paper as [16]

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Authors
Chen, Q., Espey, M. G., Krishna, M. C., Mitchell, J. B., Corpe, C. P., Buettner, G. R., Shacter, E., & Levine, M.
Affiliations
University of Iowa (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-09-12
Volume
102
Issue
38
Pages
13604-13609
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0506390102
PMC
PMC1224653
OpenAlex
W2157653515
Cited by
1,075
References
61
Citations by year
2026: 33 · 2025: 49 · 2024: 58 · 2023: 53 · 2022: 68 · 2021: 83 · 2020: 78 · 2019: 61 · 2018: 79 · 2017: 73 · 2016: 52 · 2015: 60 · 2014: 39 · 2013: 66 · 2012: 36
FWCI
23.54
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (Z01DK054506)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
vitamin C, cancer cell death, selective cytotoxicity, hydrogen peroxide, prodrugs, ascorbyl radical, apoptosis, lymphoma cells, cancer therapy
MeSH terms
Antioxidants, Ascorbic Acid, Dose-Response Relationship, Drug, Free Radicals, Humans, Hydrogen Peroxide, Lymphoma, Oxidation-Reduction, Prodrugs, Apoptosis, Cell Line, Tumor

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