Glutathione transferase (formerly GST) catalyzes the inactivation of various electrophile-producing anticancer agents via conjugation to the tripeptide glutathione. Moreover, several data link the overexpression of some GSTs, in particular GSTP1-1, to both natural and acquired resistance to various structurally unrelated anticancer drugs. Tumor overexpression of these proteins has provided a rationale for the search of GST inhibitors and GST activated cytotoxic prodrugs. In the present review we discuss the current structural and pharmacological knowledge of GST-activated cytotoxic compounds.
References
[1]
Lowenthal, R.M.; Eaton, K. Toxicity of chemotherapy. Hematol. Oncol. Clin. North Am. 1996, 10, 967–990, doi:10.1016/S0889-8588(05)70378-6.
[2]
Nielsen, D.; Maare, C.; Skovsgaard, T. Cellular resistance to anthracyclines. Gen. Pharmacol. 1996, 27, 251–255, doi:10.1016/0306-3623(95)02013-6.
[3]
Stavrovskaya, A.A. Cellular mechanisms of multidrug resistance of tumor cells. Biochem. Moscow 2000, 65, 95–106.
[4]
Arpicco, S.; Dosio, F.; Stella, B.; Cattel, L. Anticancer prodrugs: An overview of major strategies and recent developments. Curr. Top. Med. Chem. 2011, 11, 2346–2381, doi:10.2174/156802611797183221.
Commandeur, J.N.M.; Stijntjes, G.J.; Vermeulen, N.P.E. Enzymes and transport-systems involved in the formation and disposition of glutathione S-conjugates—Role in bioactivation and detoxication mechanisms of xenobiotics. Pharmacol. Rev. 1995, 47, 271–330.
[7]
Van Bladeren, P.J. Glutathione conjugation as a bioactivation reaction. Chem. Biol. Interact. 2000, 129, 61–76, doi:10.1016/S0009-2797(00)00214-3.
Ranson, H.; Rossiter, L.; Ortelli, F.; Jensen, B.; Wang, X.L.; Roth, C.W.; Collins, F.H.; Hemingway, J. Identification of a novel class of insect glutathione S-transferases involved in resistance to DDT in the malaria vector Anopheles gambiae. Biochem. J. 2001, 359, 295–304, doi:10.1042/0264-6021:3590295.
Rossjohn, J.; Polekhina, G.; Feil, S.C.; Allocati, N.; Masulli, M.; Di Ilio, C.; Parker, M.W. A mixed disulfide bond in bacterial glutathione transferase: Functional and evolutionary implications. Struct. Fold. Des. 1998, 6, 721–734, doi:10.1016/S0969-2126(98)00074-4.
[12]
DePierre, J.; Morgenstern, R. Comparison of the distribution of microsomal and cytosolic glutathione S-transferase activities in different organs of the rat. Biochem. Pharmacol. 1983, 32, 721–723, doi:10.1016/0006-2952(83)90501-4.
[13]
Pacifici, G.; Franchi, M.; Bencini, C.; Repetti, F.; Di Lascio, N.; Muraro, G. Tissue distribution of drug-metabolizing enzymes in humans. Xenobiotica 1988, 18, 849–856, doi:10.3109/00498258809041723.
[14]
Armstrong, R.N. Structure, catalytic mechanism, and evolution of the glutathione transferases. Chem. Res. Toxicol. 1997, 10, 2–18, doi:10.1021/tx960072x.
[15]
Grahn, E.; Novotny, M.; Jakobsson, E.; Gustafsson, A.; Grehn, L.; Olin, B.; Madsen, D.; Wahlberg, M.; Mannervik, B.; Kleywegt, G.J. New crystal structures of human glutathione transferase A1-1 shed light on glutathione binding and the conformation of the C-terminal helix. Acta Crystallogr. Sect. D Biol. Crystallogr. 2006, 62, 197–207.
[16]
Tan, K.L.; Chelvanayagam, G.; Parker, M.W.; Board, P.G. Mutagenesis of the active site of the human Theta-class glutathione transferase GSTT2–2: Catalysis with different substrates involves different residues. Biochem. J. 1996, 319, 315–321.
[17]
Stenberg, G.; Board, P.G.; Mannervik, B. Mutation of an evolutionarily conserved tyrosine residue in the active-site of a human class alpha-glutathione transferase. FEBS Lett. 1991, 293, 153–155, doi:10.1016/0014-5793(91)81174-7.
[18]
Kong, K.H.; Takasu, K.; Inoue, H.; Takahashi, K. Tyrosine-7 in human class-Pi glutathione-S-transferase is important for lowering the pka of the thiol-group of glutathione in the enzyme-glutathione complex. Biochem. Biophys. Res. Commun. 1992, 184, 194–197, doi:10.1016/0006-291X(92)91177-R.
[19]
Graminski, G.F.; Kubo, Y.; Armstrong, R.N. Spectroscopic and kinetic evidence for the thiolate anion of glutathione at the active site of glutathione S-transferase. Biochemistry 1989, 28, 3562–3568, doi:10.1021/bi00434a062.
[20]
Widersten, M.; Bjornestedt, R.; Mannervik, B. Involvement of the carboxyl groups of glutathione in the catalytic mechanism of human glutathione transferase A1-1. Biochemistry 1996, 35, 7731–7742, doi:10.1021/bi9601619.
[21]
Parraga, A.; Garcia-Saez, I.; Walsh, S.B.; Mantle, T.J.; Coll, M. The three-dimensional structure of a class-Pi glutathione S-transferase complexed with glutathione: The active-site hydration provides insights into the reaction mechanism. Biochem. J. 1998, 333, 811–816.
[22]
Dourado, D.; Fernandes, P.A.; Mannervik, B.; Ramos, M.J. Glutathione transferase: New model for glutathione activation. Chem. Eur. J. 2008, 14, 9591–9598, doi:10.1002/chem.200800946.
[23]
Board, P.G.; Coggan, M.; Chelvanayagam, G.; Easteal, S.; Jermiin, L.S.; Schulte, G.K.; Danley, D.E.; Hoth, L.R.; Griffor, M.C.; Kamath, A.V.; et al. Identification, characterization, and crystal structure of the omega class glutathione transferases. J. Biol. Chem. 2000, 275, 24798–24806, doi:10.1074/jbc.M001706200.
[24]
Dixon, D.P.; Davis, B.G.; Edwards, R. Functional divergence in the glutathione transferase superfamily in plants. Identification of two classes with putative functions in redox homeostasis in Arabidopsis thaliana. J. Biol. Chem. 2002, 277, 30859–30869, doi:10.1074/jbc.M202919200.
[25]
Mannervik, B.; Castro, V.M.; Danielson, U.H.; Tahir, M.K.; Hansson, J.; Ringborg, U. Expression of class Pi-glutathione transferase in human-malignant melanoma-cells. Carcinogenesis 1987, 8, 1929–1932, doi:10.1093/carcin/8.12.1929.
[26]
Hayes, J.D.; Pulford, D.J. The glutathione S-transferase supergene family: Regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit. Rev. Biochem. Mol. Biol. 1995, 30, 445–600, doi:10.3109/10409239509083491.
[27]
O’Brien, M.L.; Tew, K.D. Glutathione and related enzymes in multidrug resistance. Eur. J. Cancer 1996, 32A, 967–978.
[28]
Batist, G.; Tulpule, A.; Sinha, B.K.; Katki, A.G.; Myers, C.E.; Cowan, K.H. Overexpression of a novel anionic glutathione transferase in multidrug-resistant human-breast cancer-cells. J. Biol. Chem. 1986, 261, 5544–5549.
[29]
Sargent, J.M.; Williamson, C.; Hall, A.G.; Elgie, A.W.; Taylor, C.G. Evidence for the Involvement of the Glutathione Pathway in Drug Resistance in AML. In Drug Resistance in Leukemia and Lymphoma III; Kaspers, G.J.L., Pieters, R., Veerman, A.J.P., Eds.; Kluwer Academic/Plenum Publishers: New York, NY, USA, 1999; pp. 205–209.
[30]
Kodera, Y.; Isobe, K.; Yamauchi, M.; Kondo, K.; Akiyama, S.; Ito, K.; Nakashima, I.; Takagi, H. Expression of glutathione-S-transferase-Alpha and glutathione-S-transferase-Pi in gastric-cancer—A correlation with cisplatin resistance. Cancer Chemother. Pharmacol. 1994, 34, 203–208, doi:10.1007/BF00685078.
[31]
Adler, V.; Yin, Z.M.; Fuchs, S.Y.; Benezra, M.; Rosario, L.; Tew, K.D.; Pincus, M.R.; Sardana, M.; Henderson, C.J.; Wolf, C.R.; et al. Regulation of JNK signaling by GSTp. EMBO J. 1999, 18, 1321–1334, doi:10.1093/emboj/18.5.1321.
[32]
Sweeney, C.; Coles, B.F.; Nowell, S.; Lang, N.P.; Kadlubar, F.F. Novel markers of susceptibility to carcinogens in diet: Associations with colorectal cancer. Toxicology 2002, 181, 83–87, doi:10.1016/S0300-483X(02)00259-7.
[33]
Ruzza, P.; Rosato, A.; Rossi, C.R.; Floreani, M.; Quintieri, L. Glutathione transferases as targets for cancer therapy. Anti-Cancer Agents Med. Chem. 2009, 9, 763–777.
[34]
Gunnarsdottir, S.; Elfarra, A.A. Glutathione-Dependent metabolism of cis-3-(9H-purin-6-ylthio)acrylic acid to yield the chemotherapeutic drug 6-mercaptopurine: Evidence for two distinct mechanisms in rats. J. Pharmacol. Exp. Ther. 1999, 290, 950–957.
[35]
Elfarra, A.; Hwang, I. Targeting of 6-mercaptopurine to the kidneys. Metabolism and kidney-selectivity of S-(6-purinyl)-l-cysteine analogs in rats. Drug Metab. Dispos. 1993, 21, 841–845.
[36]
Maellaro, E.; Dominaci, S.; del Bello, B.; Valentini, M.A.; Pieri, L.; Perego, P.; Supino, R.; Zumino, F.; Lorenzini, E.; Paolicchi, A.; et al. Membrane gamma-glutamyl transpeptidase activity of melanoma cells: Effects on cellular H2O2 production, cell surface protein thiol oxidation and NF-kappa B activation status. J. Cell Sci. 2000, 113, 2671–2678.
[37]
Gunnarsdottir, S.; Rucki, M.; Elfarra, A.A. 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, doi:10.1124/jpet.301.1.77.
[38]
Gunnarsdottir, S.; Elfarra, A.A. 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. Dispos. 2004, 32, 321–327.
[39]
Eklund, B.I.; Gunnarsdottir, S.; Elfarra, A.A.; Mannervik, B. Human glutathione transferases catalyzing the bioactivation of anticancer thiopurine prodrugs. Biochem. Pharmacol. 2007, 73, 1829–1841, doi:10.1016/j.bcp.2007.02.002.
[40]
Tew, K.D. Glutathione-associated enzymes in anticancer drug-resistance. Cancer Res. 1994, 54, 4313–4320.
[41]
Eklund, B.I.; Moberg, M.; Bergquist, J.; Mannervik, B. Divergent activities of human glutathione transferases in the bioactivation of azathioprine. Mol. Pharmacol. 2006, 70, 747–754, doi:10.1124/mol.106.025288.
[42]
Cara, C.J.; Pena, A.S.; Sans, M.; Rodrigo, L.; Guerrero-Esteo, M.; Hinojosa, J.; Garcia-Paredes, J.; Guijarro, L.G. Reviewing the mechanism of action of thiopurine drugs: Towards a new paradigm in clinical practice. Med. Sci. Monit. 2004, 10, 247–254.
[43]
Shami, P.J.; Saavedra, J.E.; Wang, L.Y.; Bonifant, C.L.; Diwan, B.A.; Singh, S.V.; Gu, Y.J.; Fox, S.D.; Buzard, G.S.; Citro, M.L.; et al. JS-K, a glutathione/glutathione S-transferase-activated nitric oxide donor of the diazeniumdiolate class with potent antineoplastic activity. Mol. Cancer Ther. 2003, 2, 409–417.
[44]
Kiziltepe, T.; Hideshima, T.; Ishitsuka, K.; Ocio, E.M.; Raje, N.; Catley, L.; Li, C.Q.; Trudel, L.J.; Yasui, H.; Vallet, S.; et al. JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells. Blood 2007, 110, 709–718, doi:10.1182/blood-2006-10-052845.
[45]
Laschak, M.; Spindler, K.D.; Schrader, A.J.; Hessenauer, A.; Streicher, W.; Schrader, M.; Cronauer, M.V. JS-K, a glutathione/glutathione S-transferase-activated nitric oxide releasing prodrug inhibits androgen receptor and WNT-signaling in prostate cancer cells. BMC Cancer 2012, 12, 130:1–130:10.
Kavanagh, J.J.; Gershenson, D.M.; Choi, H.; Lewis, L.; Patel, K.; Brown, G.L.; Garcia, A.; Spriggs, D.R. Multi-Institutional phase 2 study of TLK286 (TELCYTA, a glutathione S-transferase P1-1 activated glutathione analog prodrug) in patients with platinum and paclitaxel refractory or resistant ovarian cancer. Int. J. Gynecol. Cancer 2005, 15, 593–600, doi:10.1111/j.1525-1438.2005.00114.x.
[57]
Ruzza, P.; Calderan, A.; Nassi, A.; Quintieri, L. Synthesis of GSH-linked tyrosinase-activated melanoma prodrugs. J. Pept. Sci. 2012, 18, S157.
