Restoring physiological levels of ascorbate slows tumor growth and moderates HIF‐1 pathway activity in Gulo−/− mice
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Hypoxia‐inducible factor‐1 (HIF‐1) governs cellular adaption to the hypoxic microenvironment and is associated with a proliferative, metastatic, and treatment‐resistant tumor phenotype. HIF‐1 levels and transcriptional activity are regulated by proline and asparagine hydroxylases, which require ascorbate as cofactor. Ascorbate supplementation reduced HIF‐1 activation in vitro, but only limited data are available in relevant animal models. There is no information of the effect of physiological levels of ascorbate on HIF activity and tumor growth, which was measured in this study. C57 BL/6 Gulo−/− mice (a model of the human ascorbate dependency condition) were supplemented with 3300 mg/L, 330 mg/L, or 33 mg/L of ascorbate in their drinking water before and during subcutaneous tumor growth of B16‐F10 melanoma or Lewis lung carcinoma (LL/2). Ascorbate levels in tumors increased significantly with elevated ascorbate intake and restoration of wild‐type ascorbate levels led to a reduction in growth of B16‐F10 (log phase P < 0.001) and LL/2 tumors (lag growth P < 0.001, log phase P < 0.05). Levels of HIF‐1 α protein in tumors decreased as dietary ascorbate supplementation increased for both tumor models (P < 0.001). Similarly, tumor ascorbate was inversely correlated with levels of the HIF‐1 target proteins CA‐IX, GLUT‐1, and VEGF in both B16‐F10 and LL/2 tumors (P < 0.05). The extent of necrosis was similar between ascorbate groups but varied between models (30% for B16‐F10 and 21% for LL/2), indicating that ascorbate did not affect tumor hypoxia. Our data support the hypothesis that restoration of optimal intracellular ascorbate levels reduces tumor growth via moderation of HIF‐1 pathway activity.
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In Gulo−/− mice, lung carcinoma grew slower with high-dose ascorbate (3.3 g/L drinking water or 1 g/kg daily intraperitoneal) than with low-dose ascorbate (0.33 g/L), and high-dose tumours had less HIF1α, VEGF, and microvessel density.
“lung carcinoma implanted in Gulo−/− mice grew slowly when mice were treated with high-dose ascorbate either in drinking water (3.3 g per litre) or daily intraperitoneal injection (1 gkg−1) as compared with Gulo−/− mice treated with low-dose ascorbate in drinking water (0.33 g per litre), and tumours exposed to high-dose ascorbate also had reduced expression levels of HIF1α, VEGF and reduced microv”
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Self-citation
- Authors
- Campbell, E. J., Vissers, M. C. M., Bozonet, S., Dyer, A., Robinson, B. A., & Dachs, G. U.
- Affiliations
- University of Otago (NZ)
- Canterbury District Health Board (NZ)
- Corresponding author
- Dachs, Gabi U.
- Venue
- Cancer Medicine
- Publisher
- Wiley
- Published
- 2014-10-30
- Volume
- 4
- Issue
- 2
- Pages
- 303-314
- ISSN
- 2045-7634 (ISSN-L)
- PMC
- PMC4329013
- OpenAlex
- W1992980936
- Cited by
- 59
- References
- 50
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 2 · 2022: 11 · 2021: 8 · 2020: 7 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 3 · 2015: 2
- FWCI
- 3.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancer Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Health Research Council of New Zealand (11/460)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Keywords
- vitamin C, vitamin C supplementation, HIF-1, HIF-1α, tumor growth, B16F10 melanoma, Lewis lung carcinoma, proline hydroxylase, CAIX, GLUT1, vascular endothelial growth factor, tumor hypoxia, tumor necrosis
- MeSH terms
- Animals, Ascorbic Acid, Disease Models, Animal, Dose-Response Relationship, Drug, Melanoma, Experimental, Mice, Inbred C57BL, Mice, Transgenic, Vitamins, Signal Transduction, Gene Expression Regulation, Neoplastic, Carcinoma, Lewis Lung, Cell Proliferation, Glucose Transporter Type 1, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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