Glutaminases regulate glutathione and oxidative stress in cancer
Open accessAbstract
Targeted therapies against cancer have improved both survival and quality of life of patients. However, metabolic rewiring evokes cellular mechanisms that reduce therapeutic mightiness. Resistant cells generate more glutathione, elicit nuclear factor erythroid 2-related factor 2 (NRF2) activation, and overexpress many anti-oxidative genes such as superoxide dismutase, catalase, glutathione peroxidase, and thioredoxin reductase, providing stronger antioxidant capacity to survive in a more oxidative environment due to the sharp rise in oxidative metabolism and reactive oxygen species generation. These changes dramatically alter tumour microenvironment and cellular metabolism itself. A rational design of therapeutic combination strategies is needed to flatten cellular homeostasis and accomplish a drop in cancer development. Context-dependent glutaminase isoenzymes show oncogenic and tumour suppressor properties, being mainly associated to MYC and p53, respectively. Glutaminases catalyze glutaminolysis in mitochondria, regulating oxidative phosphorylation, redox status and cell metabolism for tumour growth. In addition, the substrate and product of glutaminase reaction, glutamine and glutamate, respectively, can work as signalling molecules moderating redox and bioenergetic pathways in cancer. Novel synergistic approaches combining glutaminase inhibition and redox-dependent modulation are described in this review. Pharmacological or genetic glutaminase regulation along with oxidative chemotherapy can help to improve the design of combination strategies that escalate the rate of therapeutic success in cancer patients.
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Hypoxia and high glutathione concentrations in the tumor microenvironment greatly limit the efficacy of SDT.
“Furthermore, hypoxia and high glutathione (GSH) concentrations in the tumor microenvironment (TME) greatly limit the efficacy of SDT [24–26].”
From Nanosensitizer-assisted sonodynamic therapy for breast cancer (2025) · cites this paper as [26]
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Nanosensitizer-assisted sonodynamic therapy for breast cancer
Yu, J., Hu, J.-R., Tian, Y., Lei, Y.-M., Hu, H.-M., Lei, B.-S., Zhang, G., Sun, Y., & Ye, H.-R. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03311-3 · Cited by 43 · see citing works
- Authors
- Matés, J. M., Campos-Sandoval, J. A., de los Santos-Jiménez, J., & Márquez, J.
- Affiliations
- Instituto de Investigación Biomédica de Málaga (ES)
- Corresponding author
- Matés, José M.
- Venue
- Archives of Toxicology
- Published
- 2020-07-18
- Volume
- 94
- Issue
- 8
- Pages
- 2603-2623
- ISSN
- 0340-5761 (ISSN-L)
- 1432-0738
- OpenAlex
- W3042506370
- Cited by
- 91
- References
- 17
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 10 · 2023: 21 · 2022: 10 · 2021: 10
- FWCI
- 1.05
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Archives of Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Repositorio Institucional de la Universidad de Málaga (University of Málaga) (submittedVersion, other-oa)
- Funders
- Ministerio de Ciencia y Tecnología (RTI2018-096866-B-I00)
- Ministerio de Ciencia, Innovación y Universidades (FPU17/04084)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- glutaminase, glutathione, oxidative stress, cancer metabolism, glutaminolysis, Nrf2, antioxidant enzymes, reactive oxygen species, tumor microenvironment, c-Myc, p53, glutamate, glutaminase inhibition, combination therapy, redox homeostasis
- MeSH terms
- Animals, Antineoplastic Agents, Antioxidants, Energy Metabolism, Enzyme Inhibitors, Glutaminase, Glutamine, Glutathione, Humans, Mitochondria, Neoplasms, Signal Transduction, Oxidative Stress, Glutamic Acid, Tumor Microenvironment
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