Antioxidants Accelerate Lung Cancer Progression in Mice
Abstract
Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production.
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Protocols based on depletion of GSH or blocking uptake of the cysteine/glutamate antiporter XCT greatly impact cancer cell survival.
“while high levels of NADPH boost the metastatic ability of melanoma cells, and protocols based on depletion of GSH (isothiocyanates and aziridine derivatives that bind GSH) or based on blocking the uptake of a rate-limiting precursor of its synthesis (inhibitors of the cysteine/glutamate antiporter, XCT) greatly impact cancer cell survival67,68.”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [67]
High levels of NADPH boost the metastatic ability of melanoma cells.
“while high levels of NADPH boost the metastatic ability of melanoma cells, and protocols based on depletion of GSH (isothiocyanates and aziridine derivatives that bind GSH) or based on blocking the uptake of a rate-limiting precursor of its synthesis (inhibitors of the cysteine/glutamate antiporter, XCT) greatly impact cancer cell survival67,68.”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [67]
Antioxidants including N-acetyl l-cysteine (NAC) and vitamin E markedly increased tumor progression and cancer metastasis.
“However, in reality, previous studies have demonstrated that antioxidants, including N‐acetyl l‐cysteine (NAC) and vitamin E, markedly increased tumor progression and cancer metastasis.10, 11”
From Reactive Oxygen Species in Cancer: Current Findings and Future Directions (2021) · cites this paper as [10]
Human and animal studies have not clearly shown that antioxidants prevent or suppress cancer.
“recent results from both human and animal studies have found no clear evidence of the benefit of antioxidant treatment in preventing or suppressing cancer development.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [14]
In mouse models of lung adenocarcinoma and melanoma, antioxidants seemed to speed cancer progression and metastasis.
“antioxidant treatment even appeared to accelerate cancer progression and metastasis in mouse models of lung adenocarcinoma and melanoma14–16”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [14]
Diet supplemented with vitamin E and N-acetylcysteine resulted in increased tumor progression and suppressed survival in mouse models of KRAS and BRAF mutations in lung cancer.
“In the work, of Sayin and his group, (Sayin et al. 2014) diet supplemented with vitamin E and N-acetylcysteine resulted in increased tumor progression and suppressed survival in mouse models of KRAS and BRAF mutations in lung cancer.”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Sayin et al. 2014
Vitamin E and N-acetylcysteine act almost synergistically in tumor transcription profiles and enhance the proliferation of tumor cells accompanied by reduced expression of tumor suppressor protein p53 in human and mouse lung cancer cells.
“Although vitamin E and N-acetylcysteine are structurally different molecules, interestingly, in cellular systems they act almost synergistically in tumor transcription profiles and enhance the proliferation of tumor cells accompanied by reduced expression of tumor suppressor protein p53 and other changes in human and mouse lung cancer cells.”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Sayin et al. 2014
The effect of p53 inactivation is comparable with the effect of antioxidants accelerating the growth of tumors by disturbing the ROS-p53 axis.
“Quantitatively, the effect of p53 inactivation is comparable with the effect of antioxidants accelerating the growth of tumors by disturbing the ROS-p53 axis (Sayin et al. 2014).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Sayin et al. 2014
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- Authors
- Sayin, V. I., Ibrahim, M. X., Larsson, E., Nilsson, J. A., Lindahl, P., & Bergo, M. O.
- Affiliations
- University of Gothenburg (SE)
- Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
- Corresponding author
- Lindahl, Per
- Venue
- Science Translational Medicine
- Published
- 2014-01-29
- Volume
- 6
- Issue
- 221
- Pages
- 221ra15-221ra15
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- OpenAlex
- W2154553542
- Cited by
- 867
- References
- 42
- Citations by year
- 2026: 51 · 2025: 56 · 2024: 53 · 2023: 63 · 2022: 73 · 2021: 76 · 2020: 66 · 2019: 81 · 2018: 74 · 2017: 68 · 2016: 89 · 2015: 65 · 2014: 52
- FWCI
- 37.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Topics
- 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
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- antioxidants, N-acetylcysteine, vitamin E, lung cancer, reactive oxygen species, p53, tumor progression, BRAF, KRAS, tumor transcriptome, DNA damage, tumor cell proliferation, dietary supplementation, smokers, chronic obstructive pulmonary disease
- MeSH terms
- Acetylcysteine, Animals, Antioxidants, Disease Models, Animal, DNA Damage, Fibroblasts, Humans, Lung Neoplasms, Solubility, Vitamin E, Tumor Suppressor Protein p53, Reactive Oxygen Species, Disease Progression, Cell Line, Tumor, Cell Proliferation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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