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O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate
Open accessAbstract
Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H 2 O 2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O 2⋅- and H 2 O 2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H 2 O 2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.
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“an increased level of mitochondrial ROS in lung and glioblastoma cancer cells led to increased levels of intracellular labile iron through the upregulation of the Tf receptor (TfR), thus increasing the sensitivity of these cancer cells to ascorbate43.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [43]
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“Numerous preclinical and clinical studies indicate that parenteral injection of pharmacological ascorbate does not interfere with chemotherapy or radiotherapy and may even act synergistically43,104,105.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [43]
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“Numerous preclinical and clinical studies indicate that parenteral injection of pharmacological ascorbate does not interfere with chemotherapy or radiotherapy and may even act synergistically43,104,105.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [43]
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“This study shows that pharmacological ascorbate selectively sensitizes non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells by generating redox-active labile iron and H2O2 using in vitro cell lines and mouse models.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [43]
In the citing paper
“In addition, it shows the potential efficacy of ascorbate therapy combined with other chemotherapies in patients with GBM and NSCLC.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [43]
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Metadata
- Authors
- Schoenfeld, J. D., Sibenaller, Z. A., Mapuskar, K. A., Wagner, B. A., Cramer-Morales, K. L., Furqan, M., Sandhu, S., Carlisle, T. L., Smith, M. C., Abu Hejleh, T., Berg, D. J., Zhang, J., Keech, J., Parekh, K. R., Bhatia, S., Monga, V., Bodeker, K. L., Ahmann, L., Vollstedt, S., Brown, H., Shanahan Kauffman, E. P., Schall, M. E., Hohl, R. J., Clamon, G. H., Greenlee, J. D., Howard, M. A., Schultz, M. K., Smith, B. J., Riley, D. P., Domann, F. E., Cullen, J. J., Buettner, G. R., Buatti, J. M., Spitz, D. R., & Allen, B. G.
- Affiliations
- University of Iowa (US)
- Galera Therapeutics, Inc. (United States) (US)
- Corresponding author
- Spitz, Douglas R.
- Allen, Bryan G.
- ORCID
- Schoenfeld, Joshua D.
- Sibenaller, Zita A.
- Mapuskar, Kranti A.
- Wagner, Brett A.
- Furqan, Muhammad
- Sandhu, Sonia
- Smith, Mark C.
- Berg, Daniel J.
- Zhang, Jun
- Keech, John
- Parekh, Kalpaj R.
- Monga, Varun
- Bodeker, Kellie L.
- Vollstedt, Sandy
- Brown, Heather
- Greenlee, Jeremy D.
- Howard, Matthew A.
- Schultz, Michael K.
- Riley, Dennis P.
- Domann, Frederick E.
- Cullen, Joseph J.
- Buettner, Garry R.
- Buatti, John M.
- Spitz, Douglas R.
- Allen, Bryan G.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 31
- Issue
- 4
- Pages
- 487-500.e8
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC5497844
- OpenAlex
- W2597494578
- Cited by
- 443
- References
- 74
- Citations by year
- 2026: 27 · 2025: 34 · 2024: 44 · 2023: 52 · 2022: 59 · 2021: 56 · 2020: 61 · 2019: 45 · 2018: 45 · 2017: 20
- FWCI
- 38.88
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-08-14)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Society for Radiation Oncology (JF2014-1)
- Carver Research Program of Excellence in Redox Biology
- US NIH (R01-CA182804, R01-CA184051, R01-CA169046, U01-CA166800)
- IBM
- CCSG (P30-CA086862)
- University of Iowa Medical Scientist Training Program (T32-GM007337, T32-CA078586)
- Galera Therapeutics
- 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
- pharmacological ascorbate, reactive oxygen species, superoxide, hydrogen peroxide, mitochondrial oxidative metabolism, non-small cell lung cancer, glioblastoma
- MeSH terms
- Animals, Antineoplastic Combined Chemotherapy Protocols, Ascorbic Acid, Brain Neoplasms, Carcinoma, Non-Small-Cell Lung, Female, Glioblastoma, Humans, Hydrogen Peroxide, Iron, Lung Neoplasms, Male, Mice, Nude, Oxygen, Radiation-Sensitizing Agents, Xenograft Model Antitumor Assays, Cell Line, Tumor, Chemoradiotherapy
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