Role of glutathione in cancer progression and chemoresistance

Abstract

Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and disturbances in GSH homeostasis are involved in the etiology and progression of many human diseases including cancer. While GSH deficiency, or a decrease in the GSH/glutathione disulphide (GSSG) ratio, leads to an increased susceptibility to oxidative stress implicated in the progression of cancer, elevated GSH levels increase the antioxidant capacity and the resistance to oxidative stress as observed in many cancer cells. The present review highlights the role of GSH and related cytoprotective effects in the susceptibility to carcinogenesis and in the sensitivity of tumors to the cytotoxic effects of anticancer agents.

Figure 1

Antioxidant function of GSH. The hydrogen peroxide, produced during the aerobic metabolism, can be metabolized in the cytosol by GSH peroxidase (GPx) and catalase in peroxisomes. In order to prevent oxidative damage, the GSSG is reduced to GSH by GSSG reductase at the expense of NADPH, forming a redox cycle [17]. Organic peroxides can be reduced both by GPx and GSH-transferase (GST). In extreme conditions of oxidative stress, the ability of the cell to reduce GSSG to GSH may be less, inducing the accumulation of GSSG within the cytosol. In order to avoid a shift in the redox equilibrium, the GSSG can be actively transported out of the cell or react with protein sulfhydryl groups (PSH) and form mixed disulfides (PSSG).

Figure 2

γ-Glutamyl cycle. In the γ-glutamyl cycle, GSH is released from the cell and the ectoenzyme GGT transfers the γ-glutamyl moiety of GSH to an amino acid (aa, the best acceptor being cysteine), forming γ-glutamyl-aa and cysteinyl-glycine. The γ-glutamyl-amino acid can then be transported back into the cell and once inside can be further metabolized to release the aa and 5-oxoproline, which can be converted to glutamate and used for GSH synthesis. Cysteinyl-glycine is broken down by dipeptidase (DP) to generate cysteine and glycine. Once inside the cell, the majority of cysteine is incorporated into GSH, some being incorporated into protein, and some degraded into sulfate and taurine [18].