Glutathione and Thioredoxin Antioxidant Pathways Synergize to Drive Cancer Initiation and Progression
Open accessAbstract
Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor's ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.
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Increased intracellular levels of GSH are required for initiation and progression of various types of cancer, and inhibitors of GR behave as anticancer drugs.
“Moreover, increased intracellular levels of GSH are required for the initiation and progression of various types of cancer, and inhibitors of GR behave as anticancer drugs66”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [66]
The Summary (p. 2) says GSH synthesis is required for cancer initiation, supporting that part of the claim. It also says GSH may become dispensable later in progression; the Discussion (p. 10) reports that inhibiting the GSH pathway did not significantly impede progression of an established tumor. The paper discusses inhibitors of GSH synthesis and combined GSH–thioredoxin pathway inhibition, not GR inhibitors behaving as anticancer drugs. (LLM, conf=0.91)
Experimental — accuracy not yet measuredPrevious studies have demonstrated limitations of targeting GSH synthesis pathways either genetically via GCLM suppression or pharmacologically with buthionine sulfoximine in solid tumor models.
“Previous studies have demonstrated the limitations of targeting GSH synthesis pathways either genetically via GCLM suppression or pharmacologically with buthionine sulfoximine in solid tumor models (49).”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [49]
Inhibition of Trx2 by APR-246 can be the explanation for the caspase 2-independent effect of APR-246-induced cell death.
“Our findings indicate that inhibition of Trx2 by APR-246 can be the explanation for this effect47.”
From Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246 (2018) · cites this paper as [47]
The cancer-cell survival section (p. 8) reports cell death after combined inhibition of GSH and thioredoxin pathways using BSO with sulfasalazine or auranofin. Searches for APR-246, Trx2, and caspase-2 independence found no passage connecting those specific mechanisms to cell death, so our copy does not address the attributed explanation. (LLM, conf=0.75)
Experimental — accuracy not yet measuredGenetic or pharmacological inhibition of glutathione synthesis results in ROS accumulation and impedes cancer initiation and cell proliferation.
“Several screens for small-molecules that selectively kill transformed cells have identified compounds that reduce glutathione levels (Dolma et al., 2003; Raj et al., 2011; Trachootham et al., 2006), and genetic or pharmacological inhibition of glutathione synthesis results in ROS accumulation and impedes cancer initiation and cell proliferation (Harris et al., 2015; Lien et al., 2016).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Harris et al., 2015
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- Authors
- Harris, I. S., Treloar, A. E., Inoue, S., Sasaki, M., Gorrini, C., Lee, K. C., Yung, K. Y., Brenner, D., Knobbe-Thomsen, C. B., Cox, M. A., Elia, A., Berger, T., Cescon, D. W., Adeoye, A., Brüstle, A., Molyneux, S. D., Mason, J. M., Li, W. Y., Yamamoto, K., Wakeham, A., Berman, H. K., Khokha, R., Done, S. J., Kavanagh, T. J., Lam, C.-W., & Mak, T. W.
- Affiliations
- University Health Network (CA)
- University of Hong Kong (HK)
- Heinrich Heine University Düsseldorf (DE)
- Nagasaki University (JP)
- University of Washington (US)
- Corresponding author
- Mak, Tak W.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 27
- Issue
- 2
- Pages
- 211-222
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W1996311090
- Cited by
- 993
- References
- 10
- Citations by year
- 2026: 91 · 2025: 76 · 2024: 85 · 2023: 89 · 2022: 99 · 2021: 110 · 2020: 102 · 2019: 99 · 2018: 73 · 2017: 57 · 2016: 78 · 2015: 28 · 2012: 1
- FWCI
- 34.14
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-02-09)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- Montana State University
- Deutsche Forschungsgemeinschaft
- Fonds National de la Recherche Luxembourg
- Canadian Institutes of Health Research
- Japan Society for the Promotion of Science (26640082)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- glutathione, thioredoxin, antioxidant pathways, tumor initiation, tumor progression, GCLM, glutathione synthesis, malignant transformation, combination therapy, cancer cell death, therapeutic target
- MeSH terms
- Animals, Antioxidants, Breast Neoplasms, Female, Glutamate-Cysteine Ligase, Glutathione, Humans, Mice, Transgenic, Thioredoxins, Mammary Neoplasms, Animal, Mice, Carcinogenesis
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