The role of glutathione in cancer development and chemoresistance

Abstract

Introduction: Glutathione (GSH) is a tripeptide produced by the liver and has the ability (among others) to remove a wide range of toxins, including those produced by heavy metals, alcohol, smoking, radiation and cancer chemotherapy. Elevated GSH levels were detected in various types of tumors, along with high levels of GSH-related enzymes, such as 𝛾𝛾-glutamylcysteine ligase (GCL) and 𝛾𝛾-glutamyltranspeptidase (GGT), GSH-transporting export pumps. This makes the neoplastic tissues more resistant to chemotherapy. Therefore, the GSH system attracted the attention of scientists as a possible target for medical intervention against cancer progression and chemoresistance.

Materials and methods: The presentation represents an extensive literature review and is based on relevant scientific articles regarding the subject from medical databases.

Discussion results: The main research in the field aimed at depleting GSH by a specific inhibition of GCL, a key enzyme of GSH biosynthesis. But GSH depletion appears to be therapeutically effective when very low levels (<10% of their control values) can be achieved within the cancer cells. Thus, achievement of selective tumor GSH depletion under in vivo circumstances is a pharmacological challenge. Also, GSH synthesis and GSH synthesis-linked genes are up-regulated during oxidative stress and inflammation. Furthermore, Nrf-2 deficient cells were more susceptible to doxorubicin and BSO treatment-induced cell death than wild cells. Moreover, propyl gallate activated caspases 3, 8, and 9, and induced an increase in p53, Bax, Fas, and Fas Ligand; whereas MAPKs inhibited nuclear translocation of Nrf-2 and induced intracellular GSH depletion in human leukemia. This indicates that Nrf-2 is one of the first factors that induce cell survival under GSH depletion, which points out to this transcription factor as an attractive target in leukemia but also in other cancers sharing similar molecular mechanisms. The increase in GSH is a major contributing factor to drug resistance by binding to or reacting with, drugs, interacting with ROS, preventing damage to proteins or DNA, or by participating in DNA repair processes.

Conclusion: The modulation of cellular GSH is a double-edged sword. On one hand, enhancing the capacity of GSH and its Associated enzymes represents an aim in the search for cytoprotective strategies against cancer. On the other hand, the strategy of depleting GSH and GSH-related detoxification pathways is aimed at sensitizing cancer cells to chemotherapy.