The Interaction of the Chemotherapeutic Drug Chlorambucil with Human Glutathione Transferase A1-1: Kinetic and Structural Analysis

Karpusas, Michael; Axarli, Irene; Chiniadis, Lykourgos; Papakyriakou, Athanasios; Bethanis, Kostas; Scopelitou, Katholiki; Clonis, Yannis D.; Labrou, Nikolaos E.

doi:10.1371/journal.pone.0056337

Cited by 31 publications

(34 citation statements)

References 55 publications

(95 reference statements)

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“…Chlorambucil, as the commonly used chemotherapeutic drug, interacts with the human glutathione transferases (GSTs) and the human GSTs are the natural targets to form active complexes with chlorambucil [41, 42]. …”

Section: Resultsmentioning

confidence: 99%

Synthesis of unsymmetrical disulfanes bearing 1,2,4-triazine scaffold and their in vitro screening towards anti-breast cancer activity

et al. 2018

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A new series of 1,2,4-triazine unsymmetrical disulfanes were prepared and evaluated as anticancer activity compounds against MCF-7 human breast cancer cells with some of them acting as low micromolar inhibitors. Evaluation of the cytotoxicity using an MTT assay, the inhibition of [3H]-thymidine incorporation into DNA demonstrated that these products exhibit cytotoxic effects on breast cancer cells in vitro. The most effective compounds with 59 and 60 µM compared to chlorambucil with 47 µM were disulfanes bearing methyl and methoxy substituent in an aromatic ring. Furthermore, all new 14 compounds were obtained with 22–74% yield via mild and efficient synthesis of the sulfur–sulfur bond formation from thiols and symmetrical disulfanes using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). The molecular structure of the newly obtained compounds was confirmed by X-ray analysis. The conformational preferences of disulfide system were characterized using theoretical calculations at DFT level and statistical distributions of C–S–S–C torsion angle values based on the Cambridge Structural Database (CSD). The DFT calculations and CSD searching show two preferential conformations for C–S–S–C torsion angle close to ± 90° and relatively large freedom of rotation on S–S bond in physiological conditions. The molecular docking studies were performed using the human estrogen receptor alpha (ERα) as molecular target to find possible binding orientation and intermolecular interactions of investigated disulfanes within the active site of ERα. The S…H–S and S…H–C hydrogen bonds between sulfur atoms of bisulfide bridge and S–H and C–H groups of Cys530 and Ala350 as protein residues play crucial role in interaction with estrogen receptor for the most anticancer active disulfane.Graphical abstract Electronic supplementary materialThe online version of this article (10.1007/s00706-018-2206-y) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Synthesis of unsymmetrical disulfanes bearing 1,2,4-triazine scaffold and their in vitro screening towards anti-breast cancer activity

et al. 2018

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“…CYP3A5 and GSTA1 are associated with the detoxification of chemical stimuli, electrophilic compounds or other damage stimuli (21,22). They were also enriched in the term metabolism of xenobiotics by cytochrome P450, which plays important roles in detoxification (23).…”

Section: Discussionmentioning

confidence: 99%

Silencing TAK1 alters gene expression signatures in bladder cancer cells

et al. 2017

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Abstract. The aim of the present study was to identify the differentially expressed genes (DEGs) that are induced by the silencing of transforming growth factor-β-activated kinase 1 (TAK1) in bladder cancer cells and to analyze the potential biological effects. Dataset GSE52452 from mutant fibroblast growth factor receptor 3 (FGFR3) bladder cancer cells transfected with control siRNA or TAK1-specific siRNA was downloaded from Gene Expression Omnibus. The DEGs between the two groups were identified using Limma package following data pre-processing by Affy in Bioconductor. Enrichment analysis of DEGs was performed using the Database for Annotation, Visualization and Integrated Discovery, followed by functional annotation using TRANSFAC, TSGene and TAG databases. Integrated networks were constructed by Cytoscape and sub-networks were extracted employing BioNet, followed by enrichment analysis of DEGs in the sub-network. A total of 43 downregulated and 21 upregulated genes were obtained. The downregulated genes were enriched in five pathways, including NOD-like receptor signaling pathway and functions related to cellular response. The upregulated genes were associated with cellular developmental processes. Transcription factor EGR1 and 9 tumor-associated genes were screened from the DEGs. Among the DEGs, 10 hub nodes may represent important roles in the complex metabolic network, including EGFR, CYP3A5, MAP3K7, GSTA1, PTHLH, ALDH1A1, KCND2, EGR1, ARRB1 and ITPR1. Additionally, EGFR was correlated with ERBB2, GRB2 and PIK3R1, and these were enriched in ErbB signaling pathway and various cancer-associated pathways. Silencing TAK1 may decrease cellular response to chemical stimulus via downregulating CYP3A5, MAP3K7, GSTA1, ALDH1A1, ARRB1 and ITPR1; increase cancer cell development via upregulating EGFR, EGR1 and PTHLH; and regulate cancer metastasis through EGFR, ERBB2, GRB2 and PIK3R1.

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Section: Gsh and Drug Detoxification: The Role Of Gsh S-transferasesmentioning

confidence: 99%

“…Glutathione S-transferases (GSTs) are involved in drug detoxification through the conjugation of reactive drug metabolites to GSH [34,58,85]. The GSTs catalyze the nucleophilic attack of GSH on the electrophilic centre of a number of xenobiotic compounds, including several chemotherapeutic drugs [58,85]. Apart from conjugation of xenobiotics to GSH, many other activities are also associated with the GSTs, including steroid and leukotriene biosynthesis, peroxide degradation, double-bond cis-trans isomerization, dehydroascorbate reduction, Michael addition, and noncatalytic 'ligandin' activity (ligand binding and transport) [85].…”

Section: Gsh and Drug Detoxification: The Role Of Gsh S-transferasesmentioning

confidence: 99%

“…In the presence of GSH, the chemotherapeutic drug chlorambucil (CBL) behaves as an efficient substrate for human GSTA1-1 (hGSTA1-1). In the absence of GSH, CBL acts as an alkylating irreversible inhibitor for hGSTA1-1 [58]. The GSTs are known to be overexpressed in tumor, and naturally occurring isothiocyanates, such as benzyl isothiocyanate (BITC), are effective cancer chemopreventive compounds [95].…”

Section: Gsh and Drug Detoxification: The Role Of Gsh S-transferasesmentioning

confidence: 99%

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Regulation of Glutathione in Health and Disease with Special Emphasis on Chronic Alcoholism and Hyperglycaemia Mediated Liver Injury: A Brief Perspective

Kumar

Dey

2014

Springer Science Reviews

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Glutathione (GSH) plays a major role in the cell due to its antioxidant properties. The transcription factor Nrf2 plays an important role in the synthesis of GSH in the cell. Increased cellular GSH content leads to greatly decreased oxidative stress and toxicity. Alcoholism and hyperglycaemia both lead to liver injury, and GSH plays a crucial role in ameliorating the hepatic damage under these pathophysiological conditions. Further, GSH transferase which is involved in drug detoxification through conjugation of xenobiotics with GSH exhibits polymorphic forms which affect its detoxification efficacy. Further, GSH supplementation through NAC and UDCA and GSH depletion through BSO and DEM lessen and aggravate cellular dysfunction, respectively. Therefore, GSH regulation which occurs through several mechanisms has a very important role in maintaining or disrupting the oxidative environment of the cell.

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The Interaction of the Chemotherapeutic Drug Chlorambucil with Human Glutathione Transferase A1-1: Kinetic and Structural Analysis

Cited by 31 publications

References 55 publications

Synthesis of unsymmetrical disulfanes bearing 1,2,4-triazine scaffold and their in vitro screening towards anti-breast cancer activity

Synthesis of unsymmetrical disulfanes bearing 1,2,4-triazine scaffold and their in vitro screening towards anti-breast cancer activity

Silencing TAK1 alters gene expression signatures in bladder cancer cells

Regulation of Glutathione in Health and Disease with Special Emphasis on Chronic Alcoholism and Hyperglycaemia Mediated Liver Injury: A Brief Perspective

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