Glutathione in Cancer Cell Death

Abstract

Glutathione (L-γ-glutamyl-L-cysteinyl-glycine; GSH) in cancer cells is particularly relevant in the regulation of carcinogenic mechanisms; sensitivity against cytotoxic drugs, ionizing radiations, and some cytokines; DNA synthesis; and cell proliferation and death. The intracellular thiol redox state (controlled by GSH) is one of the endogenous effectors involved in regulating the mitochondrial permeability transition pore complex and, in consequence, thiol oxidation can be a causal factor in the mitochondrion-based mechanism that leads to cell death. Nevertheless GSH depletion is a common feature not only of apoptosis but also of other types of cell death. Indeed rates of GSH synthesis and fluxes regulate its levels in cellular compartments, and potentially influence switches among different mechanisms of death. How changes in gene expression, post-translational modifications of proteins, and signaling cascades are implicated will be discussed. Furthermore, this review will finally analyze whether GSH depletion may facilitate cancer cell death under in vivo conditions, and how this can be applied to cancer therapy.

Polyphenols delivery by polymeric materials: challenges in cancer treatment

“…Cancer cells usually show elevated GSH level increasing their antioxidant capacity and the resistance to oxidative stress (Ortega et al, 2011). Abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications.…”

Multidrug Resistance-associated Protein-1 (MRP-1)-dependent Glutathione Disulfide (GSSG) Efflux as a Critical Survival Factor for Oxidant-enriched Tumorigenic Endothelial Cells

“…This work introduces the novel concept that efficient GSSG clearance from oxidant-rich EOMA cells represents the lifeline of these cells. The current prevalent notion is that the level of GSH in the cancer cell has a direct bearing on its survival (59). Thus, depletion of cellular GSH represents a common strategy to sensitize cancer cells to inducible death (60).…”

Identification of 7,8-Diacetoxy-3-Arylcoumarin Derivative as a Selective Cytotoxic and Apoptosis-inducing Agent in a Human Prostate Cancer Cell Line

“…One way to selectively kill cancer cells without causing significant toxicity is to change the ROS levels using GSH modulation. GSH depletion causes increase susceptibility to oxidative stress and served as a potent activator of apoptosis signaling (42,43). Our evaluation of whether compound 5f induced apoptotic cell death was the result of excessive ROS production by measuring GSH levels indicates a significant GSH depletion ( Figure 7).…”