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Updated: Aug 11, 2026
Rapid Quantification of Oxidized and Reduced Forms of Glutathione Using Ortho -phthalaldehyde in Cultured Mammalian Cells In Vitro
Published on: June 28, 2024
Glutathione in cancer biology and therapy
José M Estrela1, Angel Ortega, Elena Obrador
1Department of Physiology, University of Valencia, Valencia, Spain. jose.m.estrela@uv.es
Abstract:
The glutathione (GSH) content of cancer cells is particularly relevant in regulating mutagenic mechanisms, DNA synthesis, growth, and multidrug and radiation resistance. In malignant tumors, as compared with normal tissues, that resistance associates in most cases with higher GSH levels within these cancer cells. Thus, approaches to cancer treatment based on modulation of GSH should control possible growth-associated changes in GSH content and synthesis in these cells. Despite the potential benefits for cancer therapy of a selective GSH-depleting strategy, such a methodology has remained elusive up to now. Metastatic spread, not primary tumor burden, is the leading cause of cancer death. For patient prognosis to improve, new systemic therapies capable of effectively inhibiting the outgrowth of seeded tumor cells are needed. Interaction of metastatic cells with the vascular endothelium activates local release of proinflammatory cytokines, which act as signals promoting cancer cell adhesion, extravasation, and proliferation. Recent work shows that a high percentage of metastatic cells with high GSH levels survive the combined nitrosative and oxidative stresses elicited by the vascular endothelium and possibly by macrophages and granulocytes. ?-Glutamyl transpeptidase overexpression and an inter-organ flow of GSH (where the liver plays a central role), by increasing cysteine availability for tumor GSH synthesis, function in combination as a metastatic-growth promoting mechanism. The present review focuses on an analysis of links among GSH, adaptive responses to stress, molecular mechanisms of invasive cancer cell survival and death, and sensitization of metastatic cells to therapy. Experimental evidence shows that acceleration of GSH efflux facilitates selective GSH depletion in metastatic cells.
Insights
Cancer cells with high glutathione (GSH) levels resist treatment. Strategies to reduce GSH in metastatic cells show promise for improving cancer therapy and patient outcomes.
Area of Science:
- Oncology
- Biochemistry
- Cancer Biology
Background:
- Glutathione (GSH) is crucial for cancer cell survival, regulating growth, DNA synthesis, and resistance to chemotherapy and radiation.
- Elevated GSH levels in malignant tumors compared to normal tissues contribute to multidrug and radiation resistance.
- Metastatic spread, driven by cancer cell survival under stress, is a primary cause of cancer mortality.
Purpose of the Study:
- To review the multifaceted roles of GSH in cancer, focusing on adaptive stress responses and survival mechanisms of invasive cancer cells.
- To analyze the link between GSH, cancer cell survival, and sensitization to therapeutic interventions.
- To explore strategies for selective GSH depletion in metastatic cells to improve cancer treatment efficacy.
Main Methods:
- Review of experimental evidence linking GSH metabolism to cancer cell survival and therapeutic resistance.
- Analysis of molecular mechanisms underlying cancer cell adaptation to oxidative and nitrosative stress.
- Investigation of the role of ?-glutamyl transpeptidase and inter-organ GSH flow in promoting metastasis.
Main Results:
- High GSH levels enable metastatic cancer cells to survive the oxidative and nitrosative stresses encountered in the tumor microenvironment.
- Overexpression of ?-glutamyl transpeptidase and liver-mediated GSH synthesis support tumor GSH levels and metastatic growth.
- Experimental data indicate that enhancing GSH efflux can selectively deplete GSH in metastatic cells.
Conclusions:
- Targeting GSH metabolism, particularly by promoting GSH efflux, offers a potential strategy for selective depletion in metastatic cells.
- Modulating GSH levels is critical for overcoming therapeutic resistance and inhibiting metastatic outgrowth.
- Developing therapies that selectively target GSH in metastatic cancer cells could significantly improve patient prognosis.
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