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      Glutathione S-transferase π: a potential role in antitumor therapy

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          Abstract

          Glutathione S-transferase π (GSTπ) is a Phase II metabolic enzyme that is an important facilitator of cellular detoxification. Traditional dogma asserts that GSTπ functions to catalyze glutathione (GSH)-substrate conjunction to preserve the macromolecule upon exposure to oxidative stress, thus defending cells against various toxic compounds. Over the past 20 years, abnormal GSTπ expression has been linked to the occurrence of tumor resistance to chemotherapy drugs, demonstrating that this enzyme possesses functions beyond metabolism. This revelation reveals exciting possibilities in the realm of drug discovery, as GSTπ inhibitors and its prodrugs offer a feasible strategy in designing anticancer drugs with the primary purpose of reversing tumor resistance. In connection with the authors’ current research, we provide a review on the biological function of GSTπ and current developments in GSTπ-targeting drugs, as well as the prospects of future strategies.

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          Most cited references 133

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          Glutathione Homeostasis and Functions: Potential Targets for Medical Interventions

          Glutathione (GSH) is a tripeptide, which has many biological roles including protection against reactive oxygen and nitrogen species. The primary goal of this paper is to characterize the principal mechanisms of the protective role of GSH against reactive species and electrophiles. The ancillary goals are to provide up-to-date knowledge of GSH biosynthesis, hydrolysis, and utilization; intracellular compartmentalization and interorgan transfer; elimination of endogenously produced toxicants; involvement in metal homeostasis; glutathione-related enzymes and their regulation; glutathionylation of sulfhydryls. Individual sections are devoted to the relationships between GSH homeostasis and pathologies as well as to developed research tools and pharmacological approaches to manipulating GSH levels. Special attention is paid to compounds mainly of a natural origin (phytochemicals) which affect GSH-related processes. The paper provides starting points for development of novel tools and provides a hypothesis for investigation of the physiology and biochemistry of glutathione with a focus on human and animal health.
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            The importance of glutathione in human disease.

             Danyelle Townsend (corresponding) ,  Kenneth D. Tew,  Haim Tapiero (2003)
            Reduced glutathione (GSH) is the most prevalent non-protein thiol in animal cells. Its de novo and salvage synthesis serves to maintain a reduced cellular environment and the tripeptide is a co-factor for many cytoplasmic enzymes and may also act as an important post-translational modification in a number of cellular proteins. The cysteine thiol acts as a nucleophile in reactions with both exogenous and endogenous electrophilic species. As a consequence, reactive oxygen species (ROS) are frequently targeted by GSH in both spontaneous and catalytic reactions. Since ROS have defined roles in cell signaling events as well as in human disease pathologies, an imbalance in expression of GSH and associated enzymes has been implicated in a variety of circumstances. Cause and effect links between GSH metabolism and diseases such as cancer, neurodegenerative diseases, cystic fibrosis (CF), HIV, and aging have been shown. Polymorphic expression of enzymes involved in GSH homeostasis influences susceptibility and progression of these conditions. This review provides an overview of the biological importance of GSH at the level of the cell and organism.
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              Glutathione transferases and development of new principles to overcome drug resistance.

              Chemoresistance is a multifactorial phenomenon and many studies clearly show that a coordinated expression of efflux transporter proteins and phase II conjugating enzymes in tumor cells is linked to the development of the multidrug resistance phenotype. In particular, the overexpression of glutathione S-transferases and efflux pumps in tumors may reduce the reactivity of various anticancer drugs. In recent years it has become evident that glutathione S-transferases are also involved in the control of apoptosis through the inhibition of the JNK signaling pathway. As such, the glutathione S-transferase superfamily has become the focus of extensive pharmaceutical research in attempt to generate more efficient anticancer agents. Here we present an overview of the GST inhibitors and the GST-activated pro-drugs utilized to date to overcome drug resistance. 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                23 October 2018
                : 12
                : 3535-3547
                Affiliations
                [1 ]Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and Nanjing Medical University Affiliated Cancer Hospital, Nanjing 210009, China, jifeng_feng@ 123456163.com ; cece20110622@ 123456126.com
                [2 ]Department of Biological Science, Purdue University, West Lafayette, IN, USA
                Author notes
                Correspondence: Jifeng Feng; Chen Dan, Jiangsu Cancer Hospital, 42 Baiziting Street, Nanjing, Jiangsu 210009, China, Email jifeng_feng@ 123456163.com ; cece20110622@ 123456126.com
                [*]

                These authors contributed equally to this work

                Article
                dddt-12-3535
                10.2147/DDDT.S169833
                6204874
                © 2018 Dong et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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