Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice
Open accessAbstract
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.
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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 [181]
The 'Range of Cancer Cell Sensitivity to Ascorbate-Derived Hydrogen Peroxide' section reports variable sensitivity: 75% of 43 tumor cell lines had an EC50 below 10 mM, while normal cells showed no cytotoxicity above 20 mM. It does not establish that every tested cancer cell line had an EC50 below 20 mM; that universal threshold is unsupported by the text of our copy (page unavailable). (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe 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 [181]
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- Authors
- Chen, Q., Espey, M. G., Sun, A. Y., Pooput, C., Kirk, K. L., Krishna, M. C., Khosh, D. B., Drisko, J., & Levine, M.
- Affiliations
- *Molecular and Clinical Nutrition Section and
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- National Institutes of Health (US)
- University of Kansas Medical Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-08-12
- Volume
- 105
- Issue
- 32
- Pages
- 11105-11109
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2516281
- OpenAlex
- W2119115728
- Cited by
- 854
- References
- 26
- Citations by year
- 2026: 26 · 2025: 39 · 2024: 47 · 2023: 50 · 2022: 63 · 2021: 63 · 2020: 70 · 2019: 56 · 2018: 60 · 2017: 55 · 2016: 44 · 2015: 41 · 2014: 42 · 2013: 42 · 2012: 32
- FWCI
- 38.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- 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
- 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 › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- vitamin C, pharmacologic ascorbate, pro-oxidants, hydrogen peroxide, ascorbyl radical, tumor xenografts, glioblastoma, ovarian cancer, pancreatic cancer, tumor interstitial fluid, microdialysis, cancer therapy, selective cytotoxicity
- MeSH terms
- Animals, Antineoplastic Agents, Antioxidants, Ascorbic Acid, Female, Humans, Hydrogen Peroxide, Infusions, Intravenous, Mice, Nude, Neoplasms, Prodrugs, Oxidants, Xenograft Model Antitumor Assays, Mice
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