Abstract
The major roles of glutathione (GSH) and glutathione S-transferases (GSTs) in the detoxification of xenobiotics predicts their important role in drug resistance. As such, both GSH and GSTs have been manipulated as targets in the design of novel chemotherapeutic drugs. The discovery that GSTs have additional roles in the cell as regulatory molecules in the mitogen-activated protein kinase pathways together with the more recent discovery of GSH as a regulatory posttranslational modification lend further weight to their already important roles in the anticancer drug resistance response. These findings highlight the importance of these targets in the creation of future novel anticancer drugs. This chapter gives a brief overview of the importance of both GSH and GST in the response to anticancer drug resistance, and highlights some of the anticancer drugs currently being investigated at various stages in the process from lab to clinic.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Townsend DM, Tew KD, Tapeiro H. The importance of glutathione in human disease. Biomed Pharmacother 2003; 57:145–155.
Giustarini D, Rossi R, Milzani A, Colombo R, Dalle-Donne I. S-glutathionylation: from redox regulation of protein functions to human diseases. J Cell Mol Med 2004; 8:201–212.
Adler V, Yin Z, Fuchs SY, et al. Regulation of JNK signaling by GST-π. EMBO J 1999; 18:1321–1334.
Wang T, Arifoglu P, Ronai Z, Tew KD. Glutathione S-transferase P1-1 (GSTP1-1) inhibits c-jun N-terminal kinase (JNK1) signaling through interaction with the C terminus. J Biol Chem 2001; 276:20,999–21,003.
Saitoh M, Nishitoh H, Fujii M, et al. Mammalian thioredoxin is a direct inhibitor of apoptosis signalregulating kinase (ASK) 1. EMBO J 1998; 17:2596–2606.
Adler, Yin Z, Tew KD and Ronai Z. Role of redox potential and reactive oxygen species in stress signaling. Oncogene 1999; 18:6104–6111.
Adachi T, Pimentel DR, Heibeck T, et al. S-glutathiolation of Ras mediates redox-sensitive signaling by angiotensin II in vascular smooth muscle cells. J Biol Chem 2004; 279:29,857–29,862.
Cross JV, Templeton DJ. Oxidative stress inhibits MEKK1 by site-specific glutathionylation in the ATP binding domain. Biochem J 2004; 381:675–683.
Moinova HR, Mulcahy RT. Up-regulation of the human ?-glutamylcysteine synthetase regulatory subunit gene involves binding of Nrf-2 to an electrophile response element. Biochem Biophys Res Commun 1999; 261:661–668.
Kwak MK, Kensler TW, Casero RA. Induction of phase 2 enzymes by serum oxidized polyamines through activation of Nrf2: effect of the polyamine metabolite acrolein. Biochem Biophys Res Commun 2003; 305:662–670.
Nguyen T, Sherratt PJ, Pickett CB. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 2003; 43:233–260.
Hansen JM, Watson WH, Jones DP. Compartmentation of Nrf-2 redox control: Regulation of cytoplasmic activation by glutathione and DNA binding by thioredoxin-1. Toxicol Sci 2004; 82:308–317.
Armstrong RN. Structure, catalytic mechanism and evolution of the glutathione transferases. Chem Res Toxicol 1997; 10:2–18.
Townsend DM, Tew KD. The role of glutathione S-transferase in anti-cancer drug resistance. Oncogene 2003; 22:7369–7375.
Tew KD. Glutathione-associated enzymes in anticancer drug resistance. Cancer Res 1994; 54:4313–4320.
Yin Z, Ivanov V, Habelhah H, Tew KD, Ronai Z. Glutathione S-transferase p elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases. Cancer Res 2000; 60:4053–4057.
Ichijo H, Nshida E, Irie K, etal. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 1997; 275:90–94.
Cho SG, Lee YH, Park HS, et al. Glutathione S-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1. J Biol Chem 2001; 276:12,749–12,755.
Manevich Y, Feinstein SI, Fisher AB. Activation of the antioxidant enzyme 1-CYS peroxiredoxin requires glutathionylation mediated by heterodimerization with ?GST. Proc Natl Acad Sci USA 2004; 101:3780–3785.
Kang SW, Baines IC, Rhee SG. Characterization of a mammalian peroxiredoxin that contains one conserved cysteine. J Biol Chem 1998; 273:6303–6311.
O’Dwyer PJ, LaCreta F, Nash S, et al. Phase I study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid. Cancer Res 1991; 51:6059–6065.
Bailey HH, Ripple G, Tutsch KD, et al. Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan. J Natl Cancer Inst 1997; 89:1789–1796.
O’Brien ML, Kruh GD, Tew KD. The influence of coordinate overexpression of glutathione phase II detoxification gene products on drug resistance. J Pharmacol Exp Ther 2000; 294:480–487.
Ruscoe JE, Rosario LA, Wang T, et al. Pharmacological or genetic manipulation of glutathione S-transferase P1-1 (GSTpi) influences cell proliferation pathways. J Pharmacol Exp Ther 2001; 298:339–345.
Gate L, Majumdar RS, Lunk A, Tew KD. Increased myeloproliferation in glutathione S-transferase pideficient mice is associated with a deregulation of JNK and Janus kinase/STAT pathways. J Biol Chem 2004; 279:8608–8616.
Tew KD, Monks A, Barone L, et al. Glutathione-associated enzymes in the human cell lines of the National Cancer Institute Drug Screening Program. Mol Pharmacol 1996; 50:149–159.
Gunnarsdottir S, Rucki M, Elfarra AA. Novel glutathione-dependent thiopurine prodrugs: evidence for enhanced cytotoxicity in tumor cells and for decreased bone marrow toxicity in mice. J Pharmacol Exp Ther 2002; 301:77–86.
Gunnarsdottir S, Rucki M, Phillips LA, Young KM, Elfarra AA. The glutathione-activated thiopurine prodrugs trans-6-(2-acetylvinylthio)guanine and cis-6-(2-acetylvinylthio)purine cause less in vivo toxicity than 6-thioguanine after single-and multiple-dose regimens. Mol Cancer Ther 2002; 1:1211–1220.
Gunnarsdottir S, Elfarra AA. Cytotoxicity of the novel glutathione-activated thiopurine prodrugs cis-AVTP [cis-6-(2-acetylvinylthio)purine] and trans-AVTG [trans-6-(2-acetylvinylthio)guanine] results from the national cancer institute’s anticancer drug screen. Drug Metab Disp 2004; B32:321–327.
Townsend DM, Tew KD. Cancer drugs, genetic variation and the glutathione-S-transferase gene family. Am J Pharmacogenomics 2003; 3:157–172.
Schisselbauer JC, Silber R, Papadopoulos E, Abrams K, LaCreta FP, Tew KD. Characterization of glutathione S-transferase expression in lymphocytes from chronic lymphocytic leukemia patients. Cancer Res 1990; 50:3562–3568.
Morgan AS, Sanderson PE, Borch RF, et al. Tumor efficacy and bone marrow-sparing properties of TER286, a cytotoxin activated by glutathione S-transferase. Cancer Res 1998; 58:2568–2575.
Rosario LA, O’Brien ML, Henderson CJ, Wolf CR, Tew KD (2000) Cellular responses to a glutathione S-transferase P1-1 activated prodrug. Mol Pharmacol 2000; 58:167–174.
Findlay VJ, Townsend DM, Saavedra JE, et al. Tumor cell responses to a novel glutathione S-transferase-activated nitric oxide-releasing prodrug. Mol Pharmacol 2004; 65:1070–1079.
Forman HJ, Fukuto JM, Torres M. Redox signaling: thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers. Am J Physiol 2004; 287:C246–C256.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2006 Humana Press Inc., Totowa, NJ
About this chapter
Cite this chapter
Findlay, V.J., Townsend, D.M., Tew, K.D. (2006). Glutathione and Glutathione S-Transferases in Drug Resistance. In: Teicher, B.A. (eds) Cancer Drug Resistance. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-035-5_12
Download citation
DOI: https://doi.org/10.1007/978-1-59745-035-5_12
Publisher Name: Humana Press
Print ISBN: 978-1-58829-530-9
Online ISBN: 978-1-59745-035-5
eBook Packages: MedicineMedicine (R0)