The chemistry and biology of inhibitors and pro-drugs targeted to glutathione S-transferases

Abstract

The cytosolic glutathione S-transferases are a family of structurally homologous enzymes with multiple functions, including xenobiotic detoxification, clearance of oxidative stress products, and modulation of cell proliferation and apoptosis signaling pathways. This wide-ranging functional repertoire leads to several possible therapeutic uses for isoform-specific GST inhibitors. These inhibitors may be used, in principle, to modulate tumor cell drug resistance, as sensitizers to therapeutically directed oxidative stress, to enhance cell proliferation and to augment anti-malarial drugs. With increasing knowledge of GST structural and function, rational design strategies and mechanism-based inhibitors have been exploited successfully. However, design of isoform specificity remains a significant challenge in GST inhibitor development. Strategies for further inhibitor design and their possible limitations, along with potential therapeutic uses, are summarized.

Key role for a glutathione transferase in multiple-herbicide resistance in grass weeds

“…It was therefore of interest to identify potential chemical intervention strategies that could disrupt the function of the GST and help restore herbicide sensitivity. Drawing on parallels with MDR in humans, the inhibition of drug-detoxifying GSTs has been a productive target for medicinal chemistry programs (21). Such chemical interventions have also been shown to disrupt GSTs functioning in signaling roles, for example in modulating the c-Jun-N-terminal kinase (JNK) and apoptosis signal-regulating kinase (ASK1) signaling pathways (16,22).…”

Glutathione S-Transferase Mu2 Suppresses Cancer Cell Metastasis in Non–Small Cell Lung Cancer

“…3). Within GST-M, 5 isoforms (denominated: M1-M5) have been identified (4,5). GST-M has been found to be the most effective in the detoxification following exposure to epoxides such as benzo(a)pyrene and DNA hydroperoxides (6).…”

The effect of some antineoplastic agents on glutathione S-transferase from human erythrocytes

“…GST inhibitors are emerging as promising therapeautic agents for managing the development of resistance amongst anticancer agents. For this aim, various compound groups have been determined targeting this system as GST inhibitors and investigated its effects experimentally and clinically 17,18 . These groups are combined with ethacrynic acid and its derivatives, glutathione analogues, plant polyphenolic compounds, bifunctional inhibitors, antimalarial drugs, tocopherols, haloenol lactones, 7-nitro-2,1,3-benzoksadiazole derivatives, and prodrugs activated by GST such as, TLK 286, purine analogues, and nitric oxide donors 1 .…”

“…For this reason, in regulating the efficiency of conventional electrophilic cancer drugs in chemotherapy, It came to mind that the use of GST inhibitors may be useful. Fort this purpose, various compounds were developed and were tested both experimentally and in clinic [17][18][19] . The purpose of this study is to determine GST inhibitors of antineoplastic drugs used available, especially determining those which are GSTP inhibitors, and to find out the inhibition types of the agents determined to be inhibitors.…”