Glutathione and Cancer – Lifting the Veil with Science

Unlike normal cells, cancer cells do not undergo programmed cell death, called apoptosis, allowing them to multiply continuously and without limit. In addition, these cancer cells, which have become partly foreign to the body, manage to evade the cells of the body's immune system. Alongside existing treatments for this situation, research continues into more effective and more targeted therapies and immunotherapies. Certain micronutrients thought to play a role in cancer development and progression are also being tested as "supplements" in cancer treatment research, including vitamins and antioxidants.

Antioxidants are substances that can prevent or slow the cellular damage caused by unstable molecules called free radicals, which the body produces in response to environmental and other pressures.

What Is Glutathione?

Glutathione, a naturally occurring molecule, is a powerful antioxidant important in numerous cellular processes, including cell differentiation, proliferation, and apoptosis. Its English name is glutathione, abbreviated GSH. Its chemical formula is C10H17N3O6S, and it is water-soluble.

Glutathione functions as an antioxidant in plants, animals, fungi, and some bacteria. Researchers are investigating whether disturbances in its metabolism play a role in the causes of many diseases, including cancer.

Glutathione Supplements or Serum as Cancer Treatment

Although a popular claim today suggests that glutathione supplementation helps patients receiving cancer treatment, there are not enough evidence-based scientific studies to support this. Results from laboratory and animal studies have generally required broader and more detailed human research. Studies in recent years have even drawn attention to the possibility that supplementation in particular may worsen cancer and result in death.

Another way glutathione supplements are marketed is the claim that, because digestion would destroy ordinary glutathione, we should take a "liposomal glutathione" supplement that carries it through the stomach. We are also told that we could supplement with N-acetylcysteine (NAC) and alpha-lipoic acid, which our bodies can use to make glutathione themselves... These suggestions themselves contain serious contradictions: glutathione is not something obtained from foods but a molecule produced by cells in the body.

Are Glutathione Supplements Beneficial or Harmful in Cancer? 8 Scientific Studies

Study 1: Use of Antioxidant Supplements during Breast Cancer Treatment: A Comprehensive Review (2009)

Breast cancer treatment often involves antioxidant supplement use. An estimated 45 – 80% of patients begin using antioxidant supplements after a breast cancer diagnosis. Dietary supplements with antioxidant effects also contain vitamins, minerals, phytonutrients, and other natural products.

In this study, researchers conducted a comprehensive literature review of associations between antioxidant supplement use during breast cancer treatment and patient outcomes. They reviewed articles on the use of antioxidant supplements (vitamin C, vitamin E, antioxidant combinations, multivitamins, glutamine, glutathione, melatonin, or soy isoflavones) during chemotherapy, radiotherapy, and/or hormone therapy for breast cancer, examining treatment side effects, tumor response, tumor recurrence, or survival across 22 articles.

Overall, the findings did not support any associated outcome for antioxidant supplementation during breast cancer treatment on these measures. Current evidence is insufficient to guide doctors and patients on antioxidant supplement use during breast cancer treatment. The study concluded that well-designed clinical trials and observational studies are needed to determine the short- and long-term effects of these supplements.

Study 2: The Role of Glutathione in Cancer Progression and Chemoresistance (2013)

Among the enzymatic systems involved in maintaining intracellular redox balance, glutathione plays a major role, participating not only in antioxidant defense systems but also in many metabolic processes. High glutathione levels are observed in various tumor types, making cancerous tissues more resistant to chemotherapy. In addition, the glutathione content of some tumor cells is typically associated with higher levels of glutathione-related enzymes, such as G-glutamylcysteine ligase (GCL) and G-glutamyl-transpeptidase (GGT) activity, as well as greater expression of GSH-transporting export pumps. It is therefore unsurprising that the glutathione system has attracted the attention of scientists working in drug discovery as a possible target for medical intervention against cancer progression and chemotherapy resistance.

Antioxidant therapy is thought to provide protection against cancer on the basis that an additional oxidative stimulus superimposed on constitutive oxidative stress in tumor cells should actually lead to the collapse of antioxidant systems and cell death. However, this approach has produced inadequate results because many tumors overexpress very high levels of antioxidant enzymes, leading to cancer cell resistance to drug doses. The study concluded that glutathione's role in tumor cell carcinogenesis and drug resistance was clear, but emphasized that further studies aimed at understanding glutathione-related molecular pathways may be important for designing new drug strategies to fight cancer progression and overcome chemotherapy resistance. In other words, administering glutathione supplements for cancer treatment may not work through a mechanism as simple as assumed; it may even increase the effects of existing cancer drugs by triggering chemotherapy resistance. Approaches that more specifically target glutathione metabolism should therefore be considered.

Study 3: Antioxidants in Cancer Treatment (2017)

Various clinical studies have produced conflicting results about the benefit of antioxidants in cancer treatment, calling into question their inclusion in standard treatment regimens. Vitamins E and C, selenium, carotenoids, lycopene, glutathione, soy products, and green tea extract are a few substances with antioxidant properties that have been studied in detail. This study reviewed results obtained over the past 20 years in various cancer types and treatment stages through in vitro and in vivo studies.

Despite years of research, consistent data supporting the use of antioxidants in cancer remain unclear. The inconsistencies are thought to result from numerous variables, including but not limited to endogenous (internal, produced within the body) antioxidant levels, supplemental antioxidant dose, route of administration, antioxidant type, bioavailability, timing of intervention, polymorphisms in antioxidant enzymes, the chemotherapeutic drug's mechanism of action, chemotherapy dose, and tumor pathology.  

In conclusion, antioxidants may continue to be investigated in coming years using a modified, carefully tailored approach. For now, however, despite their commercial popularity and the many studies of antioxidant supplementation, the true role of antioxidants has yet to be determined, and more research is needed into their propagative, causal, or protective nature.

Study 4: Glutathione Metabolism in Cancer Progression and Treatment Resistance (2018)

Glutathione plays a dual role in cancer progression. The removal and detoxification of carcinogens depend heavily on it, and changes in this pathway can profoundly affect cell survival. However, high glutathione levels in tumor cells may protect such cells in bone marrow, breast, colon, laryngeal, and lung cancers against drugs by conferring resistance to various chemotherapeutic agents. Glutathione's effects on oxidative stress and cancer initiation and progression are also complex because of the dual role of ROS (reactive oxygen species) in these processes. Moderate ROS levels may support survival and proliferation (progression) in the stressed tumor microenvironment by activating signaling pathways that may contribute to tumor growth. However, excessive ROS accumulation, failure of adequate clearance mechanisms, or antioxidant scarcity cause severe damage to biomolecules and trigger cell death. Cancer cells therefore need to maintain a complex balance of antioxidant levels to survive. ROS may also regulate the potential of cancer cells, particularly in melanoma and liver cancer, to metastasize to distant sites.

This information suggests that glutathione and glutathione-related components play an important role in tumor initiation, progression, and drug resistance. However, although glutathione has been known to be important in these processes for some time, its different role at each step remains unclear. Furthermore, the interaction between metabolism and the microenvironment and their relationship to tumor glutathione levels have not been examined. Glutathione also has antioxidant-independent functions in cancer cells. Research on this topic has only just begun, however, and there is still insufficient research. Regarding a better understanding of these pathways and glutathione's role in them, it is particularly important to emphasize that mechanism-based glutathione inhibitors that could subsequently be used with other drugs to effectively limit tumor growth have not yet been developed. In other words, rather than glutathione supplements in cancer treatment, glutathione inhibitors are being investigated.

Study 5: Glutathione in Ovarian Cancer: A Double-Edged Sword (2018)

This study presented some perspectives on glutathione's role in the prognosis (course) of ovarian cancer and highlighted how certain strategies underlying ovarian cancer cells' dependence on glutathione could be exploited further to improve treatment efficacy.

It has been proposed that antioxidants may benefit ovarian cancer patients as adjuncts to chemotherapy. Di Re and colleagues reported that glutathione dependence was safe, well tolerated, and highly effective in ovarian cancer patients receiving high-dose cisplatin chemotherapy. Years later, Smyth and colleagues confirmed this study, showing in a clinical trial that glutathione supplementation with cisplatin was less toxic and improved quality of life in patients with advanced ovarian cancer. However, neither study evaluated parameters such as patients' median survival, tumor recurrence, or tumor growth rate; only quality-of-life parameters were assessed. It is therefore uncertain whether glutathione supplementation affects survival. In another study, Ladas and colleagues examined the efficacy and safety of antioxidant use during cancer treatment and concluded that there was a lack of evidence that individual antioxidant vitamin supplements reduced the side effects associated with anticancer treatments.

In conclusion, there is insufficient evidence to support glutathione's use as an adjunct to chemotherapeutic drugs.

Study 6: Examining Nutrients for Glutathione Support – A Phytotherapy Approach (2019)

Optimizing glutathione levels has been proposed as a strategy for promoting health and preventing disease, but causal relationships between glutathione status and disease risk or treatment remain to be clarified, and the relationship is likely complex.

On the other hand, "the antioxidant paradox" describes the complexity of antioxidants, or a situation in which antioxidants such as glutathione may have pro-oxidant activity and cause a hormetic effect that allows the body to strengthen its own endogenous antioxidant defenses. Redox balance may, in fact, be a cause or consequence of disease, and in some situations it is difficult to know the level at which an antioxidant becomes a pro-oxidant. Therefore, much remains to be understood about the role of glutathione levels in health.

In addition, there are not yet studies of multicomponent dietary interventions specifically designed to improve glutathione status. Food-based nutritional interventions specifically designed to optimize glutathione levels may be a productive area for further research. There are also uncertainties in the evidence examining the ability of nutritional interventions to improve glutathione status; further research is needed to clarify optimal doses and methods of administration and identify subgroups of individuals most likely to respond to particular nutrients or foods. Finally, the ability of glutathione-rich foods to affect glutathione status is also an interesting possibility requiring clarification.

Study 7: Glutathione Synthesis in Cancer Cells (2020)

Control of the mechanism of glutathione synthesis in malignant tumors is not fully understood. This study discusses the characteristics of glutathione synthesis and its regulation in tumor cells.

A decrease in intracellular glutathione due to suppression of glutathione synthesis and/or increased ROS formation may be a common event in the simultaneous initiation of different forms of programmed tumor cell death. However, the mechanisms controlling glutathione synthesis in benign and malignant tumors are still not fully understood. Further investigation of the mechanisms regulating glutathione synthesis may open new avenues for exploring more selective and less toxic glutathione synthesis inhibitors that can be used with anticancer drugs to effectively suppress malignant tumor growth.

Study 8: Dietary Supplement Use during Chemotherapy and Survival Outcomes of Breast Cancer Patients Enrolled in a Cooperative Group Clinical Trial (2020)

This study examined whether supplement use during chemotherapy, particularly antioxidant use, had any effect on survival outcomes.

In conclusion, the findings support recommendations that antioxidant supplements should not be consumed during cancer treatment. The findings in this context suggest that antioxidant supplementation, like iron and vitamin B12 use during chemotherapy, may increase the risk of breast cancer recurrence and death. Insufficient evidence on the safety of dietary supplements means that definitive statements still cannot be made about this.

Conclusion

Chemotherapies are known to be specifically toxic molecules intended to destroy cancer cells, but antioxidants help repair cellular damage and may interfere with this process; it should not be overlooked that cancer cells also use antioxidants to repair themselves. Taking high doses of antioxidants such as glutathione as supplements is therefore like playing with a double-edged knife. In all the studies presented above, the complex, multiple mechanisms of glutathione have not yet been clearly elucidated, and its effects during cancer treatment in particular remain unknown, indicating that using antioxidants such as glutathione during this process is not appropriate. Their use therefore carries risks until their effects on cancer are fully understood.