HIF-Dependent Antitumorigenic Effect of Antioxidants In Vivo
Open accessAbstract
The antitumorigenic activity of antioxidants has been presumed to arise from their ability to squelch DNA damage and genomic instability mediated by reactive oxygen species (ROS). Here, we report that antioxidants inhibited three tumorigenic models in vivo. Inhibition of a MYC-dependent human B lymphoma model was unassociated with genomic instability but was linked to diminished hypoxia-inducible factor (HIF)-1 levels in a prolyl hydroxylase 2 and von Hippel-Lindau protein-dependent manner. Ectopic expression of an oxygen-independent, stabilized HIF-1 mutant rescued lymphoma xenografts from inhibition by two antioxidants: N-acetylcysteine and vitamin C. These findings challenge the paradigm that antioxidants diminish tumorigenesis primarily through decreasing DNA damage and mutations and provide significant support for a key antitumorigenic effect of diminishing HIF levels.
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NAC-treated scramble shRNA cells formed tumors, inconsistent with a previous study.
“Interestingly, our NAC treated scramble shRNA expressing cells did form tumors, which is not consistent with the aforementioned study.”
From SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production (2011) · cites this paper as Gao et al., 2007
NAC administration completely inhibits tumor formation in xenograft models.
“Previously it was reported that NAC administration completely inhibits tumor formation in xenograft models (Gao et al., 2007).”
From SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production (2011) · cites this paper as Gao et al., 2007
ROS signals are sufficient to trigger the stabilization of HIFα, and antioxidant therapy significantly inhibits tumor progression in vivo by inhibiting HIF activation.
“ROS signals are sufficient to trigger the stabilization of HIFα (21, 31), and a recent study indicates that antioxidant therapy significantly inhibits tumor progression in vivo by inhibiting HIF activation (18).”
From Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis (2008) · cites this paper as [18]
Evidence is increasing that ascorbate can inhibit tumours dependent on HIF1α.
“there is growing evidence that HIF1α-dependent tumour growth may be inhibited by ascorbate78,79.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [79]
In a mouse model of myc-driven tumorigenesis, tumor growth is inhibited by treatment with antioxidants.
“In a mouse model of myc-driven tumorigenesis, tumor growth is inhibited by treatment with antioxidants 70.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [70]
The effect of antioxidant treatment in myc-driven tumorigenesis was a result of the inhibition of HIF accumulation.
“However, the effect of antioxidant treatment was a result of the inhibition of HIF accumulation: expression of a stable HIF mutant alone could provide resistance to antioxidant treatment.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [70]
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Self-citation
- Authors
- Gao, P., Zhang, H., Dinavahi, R., Li, F., Xiang, Y., Raman, V., Bhujwalla, Z. M., Felsher, D. W., Cheng, L., Pevsner, J., Lee, L. A., Semenza, G. L., & Dang, C. V.
- Affiliations
- Johns Hopkins University (US)
- Stanford Medicine (US)
- Corresponding author
- Dang, Chi V.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2007-09
- Volume
- 12
- Issue
- 3
- Pages
- 230-238
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC2084208
- OpenAlex
- W2143182501
- Cited by
- 523
- References
- 41
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 15 · 2023: 28 · 2022: 25 · 2021: 36 · 2020: 21 · 2019: 23 · 2018: 23 · 2017: 38 · 2016: 32 · 2015: 26 · 2014: 46 · 2013: 22 · 2012: 30
- FWCI
- 11.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA057341, CA91596, CA 51497, P50CA103175, R37CA051497, R01CA091596, R01CA051497)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Keywords
- antioxidants, HIF-1, anti-tumorigenic effects, prolyl hydroxylase 2, von Hippel-Lindau protein, N-acetylcysteine, vitamin C, reactive oxygen species, genomic instability, DNA damage, lymphoma xenografts
- MeSH terms
- Acetylcysteine, Animals, Antineoplastic Agents, Antioxidants, Ascorbic Acid, Cell Line, Humans, Mice, Transgenic, Mutation, Genomic Instability, Mice, Hypoxia-Inducible Factor 1
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