Glutathione metabolism in cancer progression and treatment resistance

Glutathione (GSH) is the most abundant antioxidant found in living organisms and has multiple functions, most of which maintain cellular redox homeostasis. GSH preserves sufficient levels of cysteine and detoxifies xenobiotics while also conferring therapeutic resistance to cancer cells. However, GSH metabolism plays both beneficial and pathogenic roles in a variety of malignancies. It is crucial to the removal and detoxification of carcinogens, and alterations in this pathway can have a profound effect on cell survival. Excess GSH promotes tumor progression, where elevated levels correlate with increased metastasis. In this review, we discuss recent studies that focus on deciphering the role of GSH in tumor initiation and progression as well as mechanisms underlying how GSH imparts treatment resistance to growing cancers. Targeting GSH synthesis/utilization therefore represents a potential means of rendering tumor cells more susceptible to different treatment options such as chemotherapy and radiotherapy.

 

Conclusion

The literature reviewed in our work indicates that GSH and GSH-related moieties play a significant role in tumor initiation, progression, and drug resistance. Although it has been known for some time that GSH is important in these processes, the distinct role it plays at each step is still being elucidated. Moreover, the interplay between metabolism and the microenvironment and their relationship to tumor GSH levels has not been studied. As discussed in this review, GSH also has antioxidant-independent functions in cancer cells. However, this has only recently begun to be investigated. A better understanding of these pathways and the role of GSH in them should aid the development of mechanism-based GSH inhibitors, which can then be combinatorically used with other drugs to effectively limit tumor growth.