Glutathione Transferases: Potential Targets to Overcome Chemoresistance in Solid Tumors

Abstract

Multifunctional enzymes glutathione transferases (GSTs) are involved in the development of chemoresistance, thus representing a promising target for a novel approach in cancer treatment. This superfamily of polymorphic enzymes exhibits extraordinary substrate promiscuity responsible for detoxification of numerous conventional chemotherapeutics, at the same time regulating signaling pathways involved in cell proliferation and apoptosis. In addition to upregulated GST expression, different cancer cell types have a unique GST signature, enabling targeted selectivity for isoenzyme specific inhibitors and pro-drugs. As a result of extensive research, certain GST inhibitors are already tested in clinical trials. Catalytic properties of GST isoenzymes are also exploited in bio-activation of specific pro-drugs, enabling their targeted accumulation in cancer cells with upregulated expression of the appropriate GST isoenzyme. Moreover, the latest approach to increase specificity in treatment of solid tumors is development of GST pro-drugs that are derivatives of conventional anti-cancer drugs. A future perspective is based on the design of new drugs, which would selectively target GST overexpressing cancers more prone to developing chemoresistance, while decreasing side effects in off-target cells.

Glutathione transferase genotypes may serve as determinants of risk and prognosis in renal cell carcinoma

“…Namely, the structural resemblance of the canonical GST fold to that of the thioredoxins and glutaredoxins and the ability of many GSTs to conjugate electrophilic substrates with GSH suggests that glutathionylated proteins could be substrates for GSTs. Indeed, the immense group of proteins involved in metabolism, cytoskeletal remodeling, ion channel modulation, apoptosis and epigenetic DNA modification that are structurally and functionally modified by glutathionylation are collectively known as the “disulphide proteome” or the “glutathionome.” Another important fact regarding GSTs is their involvement in the development of chemoresistance due to detoxification of numerous chemotherapeutics . Namely, some of the conventional anti‐cancer drugs (such as chlorambucil, cyclophosphamide, melphalan, cisplatin, thiotepa, etc.)…”

“…Therefore, GSTs catalytic and regulatory roles might be considered as important contributing factors in at least three major chemoresistance mechanisms. For that reason, GSTs seem suitable for the development of novel drugs, especially since different cancer cell types have a unique GST signature, enabling targeted selectivity for isoenzyme specific inhibitors and pro‐drugs …”

“…Indeed, amino acid substitution from isoleucine (Ile) to valine (Val) changes catalytic and regulatory properties of the GSTP1 enzyme, while GSTA1 polymorphism is represented by three, apparently linked, SNPs: ‐567TOG, ‐69COT and ‐52GOA resulting in lower expression of the variant GSTA1 *B (−567G, −69 T, −52A). Similarly, SNP (C to A) in exon 4 of GSTO1 gene (GSTO1*Ala140Asp), changes its deglutathionylase and thioltransferase activity, while SNP (A to G) leading to Asn to Asp substitution at position 142 (GSTO2* Asn142Asp ) may be related to altered protein levels of GSTO2 (rs156697) . On the other hand, deletion polymorphisms in human cytosolic GSTM1 and GSTT1 genes are rather common in human population.…”

“…Multiple observations suggest that cytosolic GSTs possess roles far beyond the classical GSH‐dependent enzymatic conjugation of electrophilic xenobiotics, as well as neutralization of oxidative stress products. Namely, there are evidence on the involvement of certain GSTs in the regulation of signaling pathways, by means of interactions with members of the mitogen‐activated protein kinase (MAPK) signaling pathway (c‐Jun N‐terminal kinase, JNK; apoptosis signal‐regulating kinase, ASK; protein kinase B, Akt) and certain receptors . The ability of GSTs to participate in protein–protein interactions with signaling molecules emphasizes the multiple signaling and regulatory functions of GSTs (Figure ).…”

In vitro interaction of glutathione S‐transferase‐pi enzyme with glutathione‐coated silver sulfide quantum dots: A novel method for biodetection of glutathione S‐transferase enzyme

“…The primary role of these enzymes is the detoxification of xenobiotics and toxic endogenous compounds. These evolved enzymes show extraordinary substrate promiscuity (Pljesa-Ercegovac et al, 2018). Reaction with GSH-Ag 2 S QDs as GST substrate analogue may be due to GSTs' promiscuity properties (Pljesa-Ercegovac et al, 2018).…”