Role of Glutathione in Cancer: From Mechanisms to Therapies

Abstract

Glutathione (GSH) is the most abundant non-protein thiol present at millimolar concentrations in mammalian tissues. As an important intracellular antioxidant, it acts as a regulator of cellular redox state protecting cells from damage caused by lipid peroxides, reactive oxygen and nitrogen species, and xenobiotics. Recent studies have highlighted the importance of GSH in key signal transduction reactions as a controller of cell differentiation, proliferation, apoptosis, ferroptosis and immune function. Molecular changes in the GSH antioxidant system and disturbances in GSH homeostasis have been implicated in tumor initiation, progression, and treatment response. Hence, GSH has both protective and pathogenic roles. Although in healthy cells it is crucial for the removal and detoxification of carcinogens, elevated GSH levels in tumor cells are associated with tumor progression and increased resistance to chemotherapeutic drugs. Recently, several novel therapies have been developed to target the GSH antioxidant system in tumors as a means for increased response and decreased drug resistance. In this comprehensive review we explore mechanisms of GSH functionalities and different therapeutic approaches that either target GSH directly, indirectly or use GSH-based prodrugs. Consideration is also given to the computational methods used to describe GSH related processes for in silico testing of treatment effects.

Hyaluronic Acid-Targeted Stimuli-Sensitive Nanomicelles Co-Encapsulating Paclitaxel and Ritonavir to Overcome Multi-Drug Resistance in Metastatic Breast Cancer and Triple-Negative Breast Cancer Cells

“…GSH is expressed in higher quantities in the cytoplasm of cancer cells than normal cells [ 18 , 19 , 20 , 21 ]. GSH acts on disulfide bonds and cleaves them to the thiol bond.…”

“…Such nanocarriers can release their cargo in response to various extracellular and intracellular biological stimuli (e.g., acidic pH, upregulated enzymes, altered redox potential), along with external artificial stimuli like magnetic fields, light, and temperature. Such nanocarriers are called “smart” nanocarriers for the delivery of anticancer drugs [ 12 , 19 , 20 , 21 , 22 , 23 ]. Reduction-sensitive nanocarriers, a type of smart nanocarrier, are composed of polymers having disulfide bonds [ 24 ].…”

Immunity Depletion, Telomere Imbalance, and Cancer-associated Metabolism Pathway Aberrations in Intestinal Mucosa upon Caloric Restriction

“…Immune cell populations including progenitors and effector cells are globally reduced, suggesting increased pathogen susceptibility. If the processes controlling DNA and RNA damage induced by chemical carcinogens (49,64) become dysregulated, it increases the risk of transformation and uncontrolled proliferation of abnormal stem-like cells.…”

“…The Glutathione S-transferases (GSTs), phase II detoxification enzymes, were activated in CR mice: membrane-bound microsomal ( Mgst1, Mgst2 ) and cytosolic family members ( Gsta1, Gsta2, Gsta3, Gsta4, Gstm1, Gstm2, Gstm3, Gstm4, Gstm6, Gstk1 ). In healthy cells, it is crucial for removal and detoxification of carcinogens (64). However, GSH metabolism is associated with colorectal cancer pathogenesis (65).…”

“…GST-overexpressing phenotypes are present in many drug-resistant tumors (including breast, colon, and lung cancers) (66). We propose therapies targeting the GSH antioxidant system in tumors in combination with CR may sensitize cancer cells to treatment (64) and reduce the risk of cancerous effects in CR conditions. Mice treated with L-buthionine-sulfoximine depleted GSH levels in esophageal cancer and decreased tumor burden, inhibited cell proliferation, and activated cell apoptosis (70).…”