Glutathione S-Transferases in Cancer

Abstract

In humans, the glutathione S-transferases (GST) protein family is composed of seven members that present remarkable structural similarity and some degree of overlapping functionalities. GST proteins are crucial antioxidant enzymes that regulate stress-induced signaling pathways. Interestingly, overactive GST proteins are a frequent feature of many human cancers. Recent evidence has revealed that the biology of most GST proteins is complex and multifaceted and that these proteins actively participate in tumorigenic processes such as cell survival, cell proliferation, and drug resistance. Structural and pharmacological studies have identified various GST inhibitors, and these molecules have progressed to clinical trials for the treatment of cancer and other diseases. In this review, we discuss recent findings in GST protein biology and their roles in cancer development, their contribution in chemoresistance, and the development of GST inhibitors for cancer treatment.

The Reduction of the Combined Effects of Aflatoxin and Ochratoxin A in Piglet Livers and Kidneys by Dietary Antioxidants

“…Due to their electrophilic nature, phase-I metabolites have a potential to form stable adducts with nucleic acids and proteins, which act as cell-toxic and carcinogenic compounds [93,94]. The cytotoxic intermediates metabolites generated from Phase I are conjugated with hydrophilic moieties to form more readily excreted metabolites [95] by phase II enzymes, such as UDP-glucuronosyltransferases (UGTs), sulfotransferases, glutathione S-transferases, N-acetyltransferases, N-methyltransferases, phenol and catechol O-methyltransferase, Thiol methyltransferase and amino acid N-acyltransferase [96,97].…”

“…Glutathione S-transferases (GSTs) are dimeric enzymes (EC 2.5.1.18) that catalyze the conjugation of the reduced form of glutathione (GSH) to a broad variety of xenobiotic substrates including arene oxides, mycotoxins, lipoperoxidation-derived aldehydes, highly reactive aldehydes and other substrates [97][98][99]. GSTA1 is a cytosolic isoenzyme containing 222 amino acids from class alpha (A), based on amino acid sequence and substrate specificity of GSTs, with expression in liver and kidney.…”

Targeting Drug Chemo-Resistance in Cancer Using Natural Products

“…They can break down the glutathione part of non-polar xenobiotics and endogenous molecules converting them to more water-soluble compounds to ease their removal [159,171,172]. The GST family consists of different isozymes classes including α, Σ, Z, Ω µ, π, and θ, which are responsible for catalyzing a wide range of substances [160,173]. Moreover, it was found that a high level of GSTs are associated with developing MDR in cancer cells [61,174,175].…”

“…Moreover, it was found that a high level of GSTs are associated with developing MDR in cancer cells [61,174,175]. The antioxidant activity of GSTs mediates the chemo-resistance in tumor cells via detoxifying the anticancer drugs and, as a result, reducing cells' sensitivity to the treatment [173,176]. Several studies have shown the correlation between GST overexpression and chemo-resistance in various types of cancer, such as lung cancer [177][178][179], breast cancer [166,167,180], brain [181,182], and gastric cancer [183,184].…”

Nano-evolution and protein-based enzymatic evolution predicts novel types of natural product nanozymes of traditional Chinese medicine: cases of herbzymes of Taishan-Huangjing (Rhizoma polygonati) and Goji (Lycium chinense)

“…A class of transferases are GSTs (EC 2.5.1.18), which are phase II metabolizing enzymes and play an important role in cell detoxification and stress response [14]. The number of genes in each subclass is different in the phylogenetic tree.…”