Potential Mechanisms of Action for Vitamin C in Cancer: Reviewing the Evidence

Vissers, Margreet C. M.; Das, Andrew B.

doi:10.3389/fphys.2018.00809

Cited by 188Vitamin C and Antioxidants ResearchAntioxidant Activity and Oxidative StressCancer and biochemical research

Potential Mechanisms of Action for Vitamin C in Cancer: Reviewing the Evidence

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Vissers, Margreet C. M., Das, Andrew B.·2018·Frontiers in Physiology

DOI 10.3389/fphys.2018.00809PMC PMC6037948

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Abstract

Whether vitamin C (ascorbate) has a role to play as an anti-cancer agent has been debated for decades. Ascorbate has been used by cancer patients in an unregulated environment, either as a dietary supplement or in pharmacological doses administered by infusion, with numerous reports of clinical benefit, but in the absence of rigorous clinical trial data. The design of appropriate clinical trials has been hindered by a lack of understanding of the mechanism(s) of action that would inform the choice of effective dose, timing of administration and likely responsive cancer models. More recently, expanded understanding of the biological activities of ascorbate has led to a number of plausible hypotheses for mechanisms of anti-cancer activity. Prominent among these are the generation of significant quantities of hydrogen peroxide by the autoxidation of supra-physiological concentrations of ascorbate and stimulation of the 2-oxoglutarate-dependent dioxygenase family of enzymes (2-OGDDs) that have a cofactor requirement for ascorbate. Hydrogen peroxide generation is postulated to generate oxidative stress that preferentially targets cancer cells. The 2-OGDDs include the hydroxylases that regulate the hypoxic response, a major driver of tumor survival, angiogenesis, stem cell phenotype and metastasis, and the epigenetic histone and DNA demethylases. The latter are of particular interest, with recent studies suggesting a promising role for ascorbate in the regulation of the ten-eleven translocases (TET) DNA demethylases in hematological cancers. Support for these proposed mechanisms has come from many in vitro studies, and xenograft animal models have consistently shown an anti-cancer effect of ascorbate administration. However, decisive evidence for any particular mechanism(s) of action is not yet available from an in vivo setting. With a number of early phase clinical trials currently underway, evidence for potential mechanism(s) of action is required to inform the most appropriate study design and choice of cancer model. Hopefully such information will result in sound clinical data that will avert adding any further controversy to this already contentious debate.

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Ascorbate may boost HIF hydroxylase activity, lowering HIF1α activity and restraining tumour growth.
“This implies that ascorbate treatment may enhance the activity of HIF hydroxylases, thus inhibiting HIF1α activity and suppressing tumour growth77.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [77]

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Metabolism and requirements of ascorbic acid in man.
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Palmitoyl ascorbate and doxorubicin co-encapsulated liposome for synergistic anticancer therapy
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Ascorbate depletion increases growth and metastasis of melanoma cells in vitamin C deficient mice.
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Expression of LPA2 is associated with poor prognosis in human breast cancer and regulates HIF-1α expression and breast cancer cell growth
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Recycling of Vitamin C by Mammalian Thioredoxin Reductase
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High-Dose Intravenous Vitamin C Treatment of a Child with Neurofibromatosis Type 1 and Optic Pathway Glioma: A Case Report
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Vitamin C Modulates Doxorubicin-Induced Cardiotoxicity by Reducing P53 and Map Kinase Activation
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Targeting cancer vulnerabilities with high-dose vitamin C
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The Pharmacokinetics of Vitamin C
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Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy
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Targeting smooth muscle cell phenotypic switching in vascular disease
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Antioxidant and Anti-Tumor Effects of Dietary Vitamins A, C, and E
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Pro- and Antioxidant Effects of Vitamin C in Cancer in correspondence to Its Dietary and Pharmacological Concentrations
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Therapeutic Perspective of Vitamin C and Its Derivatives
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Glioblastoma: Current Status, Emerging Targets, and Recent Advances
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An Overview of the Antioxidant Effects of Ascorbic Acid and Alpha Lipoic Acid (in Liposomal Forms) as Adjuvant in Cancer Treatment
Attia, M., Essa, E. A., Zaki, R. M., & Elkordy, A. (2020) · Antioxidants · doi:10.3390/antiox9050359 · Cited by 106 · see citing works
Antioxidants for the Treatment of Breast Cancer: Are We There Yet?
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Iron deficiency, immunology, and colorectal cancer
Phipps, O., Brookes, M., & Al-Hassi, H. O. (2020) · Nutrition Reviews · doi:10.1093/nutrit/nuaa040 · Cited by 96 · see citing works
Multiple Effects of Ascorbic Acid against Chronic Diseases: Updated Evidence from Preclinical and Clinical Studies
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Chili peppers (Capsicum spp.): the spice not only for cuisine purposes: an update on current knowledge
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Interactions between Dietary Antioxidants, Dietary Fiber and the Gut Microbiome: Their Putative Role in Inflammation and Cancer
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High-Dose Vitamin C for Cancer Therapy
Mussa, A., Idris, R. A. M., Ahmed, N., Ahmad, S., Murtadha, A. H., Din, T. A. D. A. T., Yean, C. Y., Rahman, W. F. W. A., Lazim, N. M., Uskoković, V., et al. (2022) · Pharmaceuticals · doi:10.3390/ph15060711 · Cited by 81 · see citing works
Roles and Regulations of TET Enzymes in Solid Tumors
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The potential role of vitamin C in empowering cancer immunotherapy
Bedhiafi, T., Inchakalody, V. P., Fernandes, Q., Mestiri, S., Billa, N., Shahab Uddin, M. S., Merhi, M., & Dermime, S. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112553 · Cited by 77 · see citing works
The Role of Vitamin C in Cancer Prevention and Therapy: A Literature Review
Villagrán, M., Ferreira, J. L., Martorell, M., & Mardones, L. (2021) · Antioxidants · doi:10.3390/antiox10121894 · Cited by 73 · see citing works
Ascorbate and ferritin interactions: Consequences for iron release in vitro and in vivo and implications for inflammation
Badu-Boateng, C., & Naftalin, R. J. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.09.041 · Cited by 70 · see citing works
Understanding the Therapeutic Potential of Ascorbic Acid in the Battle to Overcome Cancer
Reang, J., Sharma, P. C., Thakur, V. K., & Majeed, J. (2021) · Biomolecules · doi:10.3390/biom11081130 · Cited by 73 · see citing works
High-Dose Vitamin C in Advanced-Stage Cancer Patients
Zasowska‐Nowak, A., Nowak, P. J., & Ciałkowska-Rysz, A. D. (2021) · Nutrients · doi:10.3390/nu13030735 · Cited by 69 · see citing works
Cytosolic and mitochondrial ROS production resulted in apoptosis induction in breast cancer cells treated with Crocin: The role of FOXO3a, PTEN and AKT signaling
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Could Ergothioneine Aid in the Treatment of Coronavirus Patients?
Cheah, I. K.-M., & Halliwell, B. B. (2020) · Antioxidants · doi:10.3390/antiox9070595 · Cited by 66 · see citing works
A Review on Electrochemical Microsensors for Ascorbic Acid Detection: Clinical, Pharmaceutical, and Food Safety Applications
Dodevska, T., Hadzhiev, D., & Shterev, I. G. (2022) · Micromachines · doi:10.3390/mi14010041 · Cited by 64 · see citing works
The role of vitamin C in epigenetic cancer therapy
Mikkelsen, S. U., Gillberg, L., Lykkesfeldt, J., & Grønbæk, K. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.03.017 · Cited by 61 · see citing works
The effects of vitamin C on respiratory, allergic and immunological diseases: An experimental and clinical-based review
Ghalibaf, M. H. E., Kianian, F., Beigoli, S., Behrouz, S., Marefati, N., Boskabady, M., & Boskabady, M. H. (2023) · Inflammopharmacology · doi:10.1007/s10787-023-01169-1 · Cited by 60 · see citing works
The small members of the JMJD protein family: Enzymatic jewels or jinxes?
Oh, S., Shin, S., & Janknecht, R. (2019) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2019.04.002 · Cited by 60 · see citing works
Mitochondrial targeted antioxidants, mitoquinone and SKQ1, not vitamin C, mitigate doxorubicin-induced damage in H9c2 myoblast: pretreatment vs. co-treatment
Sacks, B., Onal, H., Martorana, R. M., Sehgal, A., Harvey, A., Wastella, C. M., Ahmad, H., Ross, E. N., Pjetergjoka, A., Prasad, S., et al. (2021) · BMC Pharmacology and Toxicology · doi:10.1186/s40360-021-00518-6 · Cited by 56 · see citing works
Clinical remission following ascorbate treatment in a case of acute myeloid leukemia with mutations in TET2 and WT1
Das, A. B., Kakadia, P. M., Wojcik, D. P., Pemberton, L. C., Browett, P., Bohlander, S. K., & Vissers, M. C. M. (2019) · Blood Cancer Journal · doi:10.1038/s41408-019-0242-4 · Cited by 52 · see citing works
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Molecular mechanisms linking environmental toxicants to cancer development: Significance for protective interventions with polyphenols
Lagoa, R., Marques‐da‐Silva, D., Diniz, M., Daglia, M., & Bishayee, A. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.02.002 · Cited by 51 · see citing works
G6PD deficiency, redox homeostasis, and viral infections: implications for SARS-CoV-2 (COVID-19)
Yang, H., Ma, T., Tjong, W.-Y., Stern, A., & Chiu, D. T.-Y. (2021) · Free Radical Research · doi:10.1080/10715762.2020.1866757 · Cited by 47 · see citing works
Role of Antioxidant Vitamins and Other Micronutrients on Regulations of Specific Genes and Signaling Pathways in the Prevention and Treatment of Cancer
Fagbohun, O. F., Gillies, C. R., Murphy, K., & Rupasinghe, H. P. V. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076092 · Cited by 48 · see citing works
The pharmacology of vitamin C
Lykkesfeldt, J., Carr, A. C., & Tveden‐Nyborg, P. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100043 · Cited by 44 · see citing works
A review of nutrition and dietary interventions in oncology
Gray, A., Dang, B. N., Moore, T. B., Clemens, R., & Pressman, P. (2020) · SAGE Open Medicine · doi:10.1177/2050312120926877 · Cited by 45 · see citing works
Ascorbate kills breast cancer cells by rewiring metabolism via redox imbalance and energy crisis
Ghanem, A., Melzer, A. M., Zaal, E. A., Neises, L., Baltissen, D., Matar, O., Glennemeier-Marke, H., Almouhanna, F., Theobald, J., el Maaty, M. A. A., et al. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.12.012 · Cited by 38 · see citing works
Transcriptional Regulation of Ripening in Chili Pepper Fruits (Capsicum spp.)
Villa-Rivera, M. G., & Ochoa‐Alejo, N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212151 · Cited by 37 · see citing works
Vitamin C Modes of Action in Calcium-Involved Signaling in the Brain
Żylińska, L., Lisek, M., Guo, F., & Boczek, T. (2023) · Antioxidants · doi:10.3390/antiox12020231 · Cited by 38 · see citing works
Vitamin C Cytotoxicity and Its Effects in Redox Homeostasis and Energetic Metabolism in Papillary Thyroid Carcinoma Cell Lines
Tronci, L., Serreli, G., Piras, C., Frau, D. V., Dettori, T., Deiana, M., Murgia, F., Santoru, M. L., Spada, M., Leoni, V. P., et al. (2021) · Antioxidants · doi:10.3390/antiox10050809 · Cited by 36 · see citing works
The Association Between Ascorbate and the Hypoxia-Inducible Factors in Human Renal Cell Carcinoma Requires a Functional Von Hippel-Lindau Protein
Wohlrab, C., Vissers, M. C. M., Phillips, E., Morrin, H., Robinson, B. A., & Dachs, G. U. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00574 · Cited by 35 · see citing works
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Evaluation of anti-cancer and anti-metastatic effects of folate-PEGylated niosomes for co-delivery of letrozole and ascorbic acid on breast cancer cells
Bourbour, M., Khayam, N., Noorbazargan, H., Yaraki, M. T., Lalami, Z. A., Akbarzadeh, I., Yeganeh, F. E., Dolatabadi, A., rad, F. M., & Tan, Y. N. (2022) · Molecular Systems Design & Engineering · doi:10.1039/d2me00024e · Cited by 35 · see citing works
Microgreens: Cultivation practices, bioactive potential, health benefits, and opportunities for its utilization as value-added food
Gunjal, M., Singh, J., Kaur, J., Kaur, S., Nanda, V., Sharma, A., & Rasane, P. (2024) · Food Bioscience · doi:10.1016/j.fbio.2024.105133 · Cited by 34 · see citing works
Chromosomal Instability in Acute Myeloid Leukemia
Lisboa, M. D. O., Brofman, P. R. S., Schmid-Braz, A. T., Pozzo, A. R., & Mai, S. (2021) · Cancers · doi:10.3390/cancers13112655 · Cited by 33 · see citing works
The Involvement of Ascorbic Acid in Cancer Treatment
Guo, D., Liao, Y., Na, J., Wu, L., Yin, Y., Mi, Z., Fang, S., Liu, X., & Huang, Y. (2024) · Molecules · doi:10.3390/molecules29102295 · Cited by 31 · see citing works
Association of vitamin C intake with breast cancer risk and mortality: a meta-analysis of observational studies
Zhang, D., Xu, P., Li, Y., Wei, B., Yang, S., Zheng, Y., Lyu, L., Deng, Y., Zhai, Z., Li, N., et al. (2020) · Aging · doi:10.18632/aging.103769 · Cited by 31 · see citing works
Long-Term Exposure to Nitrate and Trihalomethanes in Drinking Water and Prostate Cancer: A Multicase–Control Study in Spain (MCC-Spain)
Donat‐Vargas, C., Kogevinas, M., Castaño‐Vinyals, G., Pérez‐Gómez, B., Llorca, J., Vanaclocha‐Espí, M., Fernández‐Tardón, G., Costas, L., Aragonés, N., Gómez‐Acebo, I., et al. (2023) · Environmental Health Perspectives · doi:10.1289/ehp11391 · Cited by 31 · see citing works
Cell signaling pathways based on vitamin C and their application in cancer therapy
Fan, D., Liu, X., Shen, Z., Wu, P., Zhong, L., & Lin, F. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114695 · Cited by 30 · see citing works
Potent anti‐inflammatory Terminalia chebula fruit showed in vitro anticancer activity on lung and breast carcinoma cells through the regulation of Bax/Bcl‐2 and caspase‐cascade pathways
Shendge, A. K., Sarkar, R., & Mandal, N. (2020) · Journal of Food Biochemistry · doi:10.1111/jfbc.13521 · Cited by 31 · see citing works
Vitamin C Administration by Intravenous Infusion Increases Tumor Ascorbate Content in Patients With Colon Cancer: A Clinical Intervention Study
Dachs, G. U., Gandhi, J., Wohlrab, C., Carr, A. C., Morrin, H. R., Pullar, J. M., Bayer, S. B., Eglinton, T., Robinson, B. A., & Vissers, M. C. M. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.600715 · Cited by 30 · see citing works
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Minerals and Cancer: Overview of the Possible Diagnostic Value
Venturelli, S., Leischner, C., Helling, T., Renner, O., Burkard, M., & Marongiu, L. (2022) · Cancers · doi:10.3390/cancers14051256 · Cited by 30 · see citing works
Vitamin C: A stem cell promoter in cancer metastasis and immunotherapy
Fu, J., Wu, Z., Liu, J., & Wu, T. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110588 · Cited by 28 · see citing works
Vitamins and Uterine Fibroids: Current Data on Pathophysiology and Possible Clinical Relevance
Ciebiera, M., Ali, M. K., Zgliczyńska, M., Skrzypczak, M., & Al-Hendy, A. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155528 · Cited by 28 · see citing works
Emerging epigenetic therapeutics for myeloid leukemia: modulating demethylase activity with ascorbate
Das, A. B., Smith-Díaz, C. C., & Vissers, M. C. M. (2020) · Haematologica · doi:10.3324/haematol.2020.259283 · Cited by 25 · see citing works
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Biocompatible hole scavenger–assisted graphene oxide dots for photodynamic cancer therapy
Shih, C.-Y., Huang, W.-L., Chiang, I.-T., Su, W., & Teng, H. (2021) · Nanoscale · doi:10.1039/d1nr01476e · Cited by 25 · see citing works
The Antioxidant and Antiproliferative Activities of 1,2,3-Triazolyl-L-Ascorbic Acid Derivatives
Harej, A., Meščić, A., Stepanić, V., Klobučar, M., Pavelić, K., Pavelić, S. K., & Raić‐Malić, S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194735 · Cited by 24 · see citing works
Peroxiredoxin 2 oxidation reveals hydrogen peroxide generation within erythrocytes during high-dose vitamin C administration
Pearson, A. G., Pullar, J. M., Cook, J., Spencer, E. S., Vissers, M. C. M., Carr, A. C., & Hampton, M. B. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101980 · Cited by 23 · see citing works
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Prophylactic Treatment with Vitamins C and B2 for Methotrexate-Induced Gastrointestinal Mucositis
Ferreira, A. R. D. S., Wardill, H. R., Havinga, R., Tissing, W. J. E., & Harmsen, H. J. M. (2020) · Biomolecules · doi:10.3390/biom11010034 · Cited by 23 · see citing works
Effects of vitamin C on osteoblast proliferation and osteosarcoma inhibition using plasma coated hydroxyapatite on titanium implants
Sarkar, N., Morton, H., & Bose, S. (2020) · Surface and Coatings Technology · doi:10.1016/j.surfcoat.2020.125793 · Cited by 22 · see citing works
Ascorbate-induced oxidative stress mediates TRP channel activation and cytotoxicity in human etoposide-sensitive and -resistant retinoblastoma cells
Oronowicz, J., Reinhard, J., Reinach, P. S., Ludwiczak, S., Luo, H., Salem, M. H. O. B., Kraemer, M. M., Biebermann, H., Kakkassery, V., & Mergler, S. (2020) · Laboratory Investigation · doi:10.1038/s41374-020-00485-2 · Cited by 20 · see citing works
Cancer Cell Detection‐Based on Released Hydrogen Peroxide Using a Non‐Modified Closed Bipolar Electrochemical System
Shokouhi, M., & Mehrgardi, M. A. (2020) · ChemElectroChem · doi:10.1002/celc.202000535 · Cited by 20 · see citing works
Therapeutic Potential of Reactive Oxygen Species: State of the Art and Recent Advances
Graceffa, V. (2020) · SLAS TECHNOLOGY · doi:10.1177/2472630320977450 · Cited by 20 · see citing works
Ascorbate is a multifunctional micronutrient whose synthesis is lacking in primates
Fujii, J. (2021) · Journal of Clinical Biochemistry and Nutrition · doi:10.3164/jcbn.20-181 · Cited by 19 · see citing works
Exploring the Role of Metabolites in Cancer and the Associated Nerve Crosstalk
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Authors: Vissers, M. C. M., & Das, A. B.
Affiliations: University of Otago (NZ)
Corresponding author: Vissers, Margreet C. M.
ORCID: Vissers, Margreet C. M.
Das, Andrew B.
Venue: Frontiers in Physiology
Publisher: Frontiers Media SA
Published: 2018-07-03
Volume: 9
Pages: 809-809
ISSN: 1664-042X (ISSN-L)
DOI: 10.3389/fphys.2018.00809
PMC: PMC6037948
OpenAlex: W2807800532
Cited by: 188
References: 191
Citations by year: 2026: 9 · 2025: 17 · 2024: 34 · 2023: 21 · 2022: 26 · 2021: 39 · 2020: 28 · 2019: 10 · 2018: 4
FWCI: 2.60
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: Frontiers in Physiology (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: University of Otago
Topics: Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
Keywords: vitamin C, anticancer mechanism, hydrogen peroxide, 2-oxoglutarate-dependent dioxygenase, oxidative stress, tumor hypoxia, hydroxylase, DNA demethylase, hematologic cancer, dietary supplements, clinical trial design

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Potential Mechanisms of Action for Vitamin C in Cancer: Reviewing the Evidence

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