- Email: [email protected]
Is there a role for glyoxalase I inhibitors as antitumor drugs?
PERSPECTIVE Is there a role for glyoxalase I inhibitors as antitumor drugs? Kenneth D.Tew Department of Pharmacology, Fox Chase Cancer Center, Philadelphia PA, USA
n an era of high throughput, microarray-based, drugtarget selection processes, the consideration of an old favorite encompassing the glyoxalase system could be considered somewhat anachronistic. To gain historical perspective, one need only review the extensive, and extended, literature on the involvement of methylglyoxal and the glyoxalase system in cell growth and division. As far back as 1913, two groups described the enzymes responsible for catalysis of α-oxoaldehydes into α-hydroxyacids.1,2 There followed a period during which a functional role for this enzyme system was sought, either in intermediary metabolism or in control of proliferation. By far the most active protagonist of the latter concept was Albert Szent-Gyorgyi who published profusely on the ‘promine/retine’ theory of control of cell division (for example, see ref.3). Briefly, this theory addressed the principle that methylglyoxal, through modification of specific target proteins, could act as a trigger for cell division. Cellular concentrations of methylglyoxal were controlled by glyoxalase and the inability of tumor cells to control the kinetics of this system were thought to underlie diseases such as cancer. In recent times, it has become apparent that the control of cell division is multifactorial, but Szent-Gyorgyi’s treatise has provided an important framework for current studies on how interference with the glyoxalase system may influence cell division. The pathway whereby methylglyoxal is detoxified to lactic acid is shown in Figure 1. Because of the high respiratory activity in rapidly proliferating tumor cells, a significant and broad interest in targeting glyoxalase I with small molecule inhibitors has persisted over the last three decades. While problems with the design of specific inhibitors has to some degree limited progress, a recent paper by Sakamoto et al.4 provides further impetus to the possible therapeutic implications of glyoxalase inhibition. Using cDNA subtractive hybridization with mRNA from drug sensitive and resistant human monocytic leukemic cells, these authors identified glyoxalase I as an overexpressed component of these, and
I
other, drug resistant cell lines.Transfection of glyoxlase I into Jurkat cells prevented caspase activation and apoptosis caused by etoposide or adriamycin. Moreover, co-treatment with S-p-bromobenzylglutathione cyclopentyl ester (a glyoxalase I inhibitor) enhanced etoposide-induced apoptosis in drug-resistant cells. From these collective data, the authors conclude that inhibitors of glyoxalase I may be useful drugs in reversing drug resistance. Methylglyoxal may itself induce toxicity by binding to cellular nucleophiles including nucleic acids and proteins. Indeed, methylglyoxal has been used as an exogenous antitumor agent, although the concentrations required and the lack of a meaningful therapeutic index have always limited its utility. The more rational endeavor of elevating endogenous methylglyoxal by interference with the regulating enzymes has provided a number of potential leads. The primary sequence5 and three-dimensional structure6 of glyoxalase I have been determined and such information should prove useful in the design of novel targeting agents. In addition, aberrant glyoxalase I expression has been associated with tumorigenesis and drug resistance7 and the presence of an insulin response element in the regulatory region of glyoxalase I8 may be pertinent to some of the clinical symptoms of diabetes.These links with two major chronic disease states serve to enhance the potential importance of glyoxalase I as a drug target. Some of the earliest studies by Vince et al.9 recognized the possibility of substituting glutathione to achieve a site directed inhibition of glyoxalase I. These approaches have been extended to include such compounds as diesters of bromobenzyl derivatives of glutathione (Fig. 2)10 and more recently S-(N-Aryl-N-hydroxycarbamoyl) glutathione derivatives.11 Lead compounds with possible pharmaceutical potential include an enediol analogue S-(N-p-chlorophenyl-N -hydroxycarbamoyl) glutathione diethyl ester.11 The latter agent is a powerful mechanism based, competitive inhibitor of glyoxalase I. Perhaps most importantly, this drug has been shown to possess both in vitro and in vivo antitumor potential at micromolar concentrations.12 Preclinical efficacy and pharmacokinetic studies will help to determine whether this, or a similarly designed drug, may progress to phase I clinical testing. Other derivatives of glutathione include peptidomimetics such as TLK199 (Fig. 2).The de-esterified form of this drug is an inhibitor of glutathione S-transferase P1–1.13 Because of its specificity for the glutathione-binding site, it is also an effective inhibitor of glyoxalase I.14 In general, glutathione-based therapeutics suffer from the problem that they may inhibit all enzymes that possess a
Fig. 1 The glyoxalase cycle.
2000 Harcourt Publishers Ltd Drug Resistance Updates (2000) 3, 263–264 doi: 10.1054/drup.2000.0155, available online at http://www.idealibrary.com on
263
Tew REFERENCES
Fig. 2 Chemical structures of inhibitors of glyoxalase I.Top panel:TLK 199, γ-glutamyl-S-(benzyl) cysteinyl-R-phenyl glycine diethyl ester. Bottom panel: S-(4-bromobenzyl) glutathione. 12
glutathione-binding site. This could influence synthetic and homeostatic thiol pathways.Testing of such drugs will necessarily have to consider possible untoward pleiotropic effects. Realistically, the design and implementation of clinical approaches to modulate drug resistance have been neither straightforward nor successful. Based initially on the promise of reversing the multidrug-resistant phenotype,15 small molecule inhibitors have been produced in large numbers.16,17 Positive clinical trials either with these agents or with modulators of other drug-resistance mechanisms have been limited. Thus, while Sakamoto et al. raise the possibility of modulating glyoxalase I-mediated resistance, perhaps a more practical approach would be to continue with efforts to design pharmacologically viable glyoxalase I inhibitors. Despite the long history of glyoxalase studies, it may yet prove to be a viable anticancer drug target. Received 19 July 2000; Revised 26 July 2000; Accepted 26 July 2000 Correspondence to: Kenneth D.Tew, Department of Pharmacology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia PA 19111, USA.Tel: +1 215 728 3137; Fax: +1 215 728 4333; E-mail [email protected]
264
Drug Resistance Updates (2000) 3, 263–264
2000 Harcourt Publishers Ltd
1. Neuberg C.The destruction of lactic aldehyde and methylglyoxal by animal organs. Biochem Z 1913;49:502–506. 2. Dakin HD, Dudley HW.An enzyme concerned with the formation of hydroxy-acids from ketonic aldehydes. J Biol Chem 1913;14:155–157. 3. Szent-Gyorgyi A. Constituents of the thymus gland and their relation to growth, fertility, muscle, and cancer. Proc Natl Acad Sci USA 1962;48:1439–1442. 4. Sakamoto H, Mashima T, Kizaki A et al. Glyoxalase I is involved in resistance of human leukemia cells to antitumor agent-induced apoptosis. Blood 2000;95:3214–3218. 5. Ranganathan S,Walsh ES, Godwin AK,Tew KD. Cloning, sequencing and expression of human colon glyoxalase-I. J Biol Chem 1993;268:5661–5667. 6. Cameron AD, Olin B, Ridderstrom M, Mannervik B, Jones A. Crystal structure of human glyoxalase I – Evidence for gene duplication and 3D domain swapping. EMBO J 1997;16: 3386–3395. 7. Ranganathan S,Walsh ES,Tew KD. Glyoxalase-I in detoxification studies using a glyoxalase-I transfectant cell line. Biochem J 1995;309:127–131. 8. Ranganathan S, Ciaccio PJ,Walsh ES,Tew KD. Genomic sequence of human glyoxalase-I: analysis of promoter activity and its regulation. Gene 1999;240:149–155. 9. Vince R, Daluge S,Wadd WB. Studies on the inhibition of glyoxalase I by S-substituted glutathiones. J Med Chem 1971;14:402–404. 10. Thornalley PJ, Ladan MJ, Ridgeway SJS, Kang Y.Antitumor activity of S-p-promobenzyl) glutathione diesters in vitro: a structure activity study. J Med Chem 1996;39:3409–3411. 11. Kavarana MJ, Kovaleva EG, Creighton DJ,Wollman MB, Eiseman JL. Mechanism-based competitive inhibitors of glyoxalase I: intracellular delivery, in vitro antitumor activities, and stabilities in human serum and mouse serum. J Med Chem 1999;42:221–228. 12. Creighton DJ, Hamilton DS, Kavarana MJ, Sharkey EM, Eiseman JL. Glyoxalase enzyme system as a potential target for antitumor drug development. Drugs of the Future 2000;25:385–392. 13. Morgan AS, Ciaccio PJ,Tew KD, Kauvar LM. Isozyme specific GST inhibitors potentiate drug sensitivity in cultured human tumor cell lines. Cancer Chemother Pharmacol 1996;37: 363–370. 14. Johansson AS, Ridderstrom M, Mannervik B.The human glutathione transferase P1-1 specific inhibitor TER117 designed for overcoming cytostatic-drug resistance is also a strong inhibitor of glyoxalase I. Mol Pharmacol 2000;57:619–624. 15. Sandor V, Fojo T, Bates SE. Future perspectives for the development of P-glycoprotein modulators. Drug Resistance Updates 1998;1:190–200. 16. McLellan LI,Wolf CR. Glutathione and glutathione-dependent enzymes in cancer drug resistance. Drug Resistance Updates 1999;2:153–164. 17. Tew KD, Houghton JA, Houghton PJ. Preclinical and clinical modulation of anticancer drugs. Boca Raton, Florida: CRC Press, 1993.
n an era of high throughput, microarray-based, drugtarget selection processes, the consideration of an old favorite encompassing the glyoxalase system could be considered somewhat anachronistic. To gain historical perspective, one need only review the extensive, and extended, literature on the involvement of methylglyoxal and the glyoxalase system in cell growth and division. As far back as 1913, two groups described the enzymes responsible for catalysis of α-oxoaldehydes into α-hydroxyacids.1,2 There followed a period during which a functional role for this enzyme system was sought, either in intermediary metabolism or in control of proliferation. By far the most active protagonist of the latter concept was Albert Szent-Gyorgyi who published profusely on the ‘promine/retine’ theory of control of cell division (for example, see ref.3). Briefly, this theory addressed the principle that methylglyoxal, through modification of specific target proteins, could act as a trigger for cell division. Cellular concentrations of methylglyoxal were controlled by glyoxalase and the inability of tumor cells to control the kinetics of this system were thought to underlie diseases such as cancer. In recent times, it has become apparent that the control of cell division is multifactorial, but Szent-Gyorgyi’s treatise has provided an important framework for current studies on how interference with the glyoxalase system may influence cell division. The pathway whereby methylglyoxal is detoxified to lactic acid is shown in Figure 1. Because of the high respiratory activity in rapidly proliferating tumor cells, a significant and broad interest in targeting glyoxalase I with small molecule inhibitors has persisted over the last three decades. While problems with the design of specific inhibitors has to some degree limited progress, a recent paper by Sakamoto et al.4 provides further impetus to the possible therapeutic implications of glyoxalase inhibition. Using cDNA subtractive hybridization with mRNA from drug sensitive and resistant human monocytic leukemic cells, these authors identified glyoxalase I as an overexpressed component of these, and
I
other, drug resistant cell lines.Transfection of glyoxlase I into Jurkat cells prevented caspase activation and apoptosis caused by etoposide or adriamycin. Moreover, co-treatment with S-p-bromobenzylglutathione cyclopentyl ester (a glyoxalase I inhibitor) enhanced etoposide-induced apoptosis in drug-resistant cells. From these collective data, the authors conclude that inhibitors of glyoxalase I may be useful drugs in reversing drug resistance. Methylglyoxal may itself induce toxicity by binding to cellular nucleophiles including nucleic acids and proteins. Indeed, methylglyoxal has been used as an exogenous antitumor agent, although the concentrations required and the lack of a meaningful therapeutic index have always limited its utility. The more rational endeavor of elevating endogenous methylglyoxal by interference with the regulating enzymes has provided a number of potential leads. The primary sequence5 and three-dimensional structure6 of glyoxalase I have been determined and such information should prove useful in the design of novel targeting agents. In addition, aberrant glyoxalase I expression has been associated with tumorigenesis and drug resistance7 and the presence of an insulin response element in the regulatory region of glyoxalase I8 may be pertinent to some of the clinical symptoms of diabetes.These links with two major chronic disease states serve to enhance the potential importance of glyoxalase I as a drug target. Some of the earliest studies by Vince et al.9 recognized the possibility of substituting glutathione to achieve a site directed inhibition of glyoxalase I. These approaches have been extended to include such compounds as diesters of bromobenzyl derivatives of glutathione (Fig. 2)10 and more recently S-(N-Aryl-N-hydroxycarbamoyl) glutathione derivatives.11 Lead compounds with possible pharmaceutical potential include an enediol analogue S-(N-p-chlorophenyl-N -hydroxycarbamoyl) glutathione diethyl ester.11 The latter agent is a powerful mechanism based, competitive inhibitor of glyoxalase I. Perhaps most importantly, this drug has been shown to possess both in vitro and in vivo antitumor potential at micromolar concentrations.12 Preclinical efficacy and pharmacokinetic studies will help to determine whether this, or a similarly designed drug, may progress to phase I clinical testing. Other derivatives of glutathione include peptidomimetics such as TLK199 (Fig. 2).The de-esterified form of this drug is an inhibitor of glutathione S-transferase P1–1.13 Because of its specificity for the glutathione-binding site, it is also an effective inhibitor of glyoxalase I.14 In general, glutathione-based therapeutics suffer from the problem that they may inhibit all enzymes that possess a
Fig. 1 The glyoxalase cycle.
2000 Harcourt Publishers Ltd Drug Resistance Updates (2000) 3, 263–264 doi: 10.1054/drup.2000.0155, available online at http://www.idealibrary.com on
263
Tew REFERENCES
Fig. 2 Chemical structures of inhibitors of glyoxalase I.Top panel:TLK 199, γ-glutamyl-S-(benzyl) cysteinyl-R-phenyl glycine diethyl ester. Bottom panel: S-(4-bromobenzyl) glutathione. 12
glutathione-binding site. This could influence synthetic and homeostatic thiol pathways.Testing of such drugs will necessarily have to consider possible untoward pleiotropic effects. Realistically, the design and implementation of clinical approaches to modulate drug resistance have been neither straightforward nor successful. Based initially on the promise of reversing the multidrug-resistant phenotype,15 small molecule inhibitors have been produced in large numbers.16,17 Positive clinical trials either with these agents or with modulators of other drug-resistance mechanisms have been limited. Thus, while Sakamoto et al. raise the possibility of modulating glyoxalase I-mediated resistance, perhaps a more practical approach would be to continue with efforts to design pharmacologically viable glyoxalase I inhibitors. Despite the long history of glyoxalase studies, it may yet prove to be a viable anticancer drug target. Received 19 July 2000; Revised 26 July 2000; Accepted 26 July 2000 Correspondence to: Kenneth D.Tew, Department of Pharmacology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia PA 19111, USA.Tel: +1 215 728 3137; Fax: +1 215 728 4333; E-mail [email protected]
264
Drug Resistance Updates (2000) 3, 263–264
2000 Harcourt Publishers Ltd
1. Neuberg C.The destruction of lactic aldehyde and methylglyoxal by animal organs. Biochem Z 1913;49:502–506. 2. Dakin HD, Dudley HW.An enzyme concerned with the formation of hydroxy-acids from ketonic aldehydes. J Biol Chem 1913;14:155–157. 3. Szent-Gyorgyi A. Constituents of the thymus gland and their relation to growth, fertility, muscle, and cancer. Proc Natl Acad Sci USA 1962;48:1439–1442. 4. Sakamoto H, Mashima T, Kizaki A et al. Glyoxalase I is involved in resistance of human leukemia cells to antitumor agent-induced apoptosis. Blood 2000;95:3214–3218. 5. Ranganathan S,Walsh ES, Godwin AK,Tew KD. Cloning, sequencing and expression of human colon glyoxalase-I. J Biol Chem 1993;268:5661–5667. 6. Cameron AD, Olin B, Ridderstrom M, Mannervik B, Jones A. Crystal structure of human glyoxalase I – Evidence for gene duplication and 3D domain swapping. EMBO J 1997;16: 3386–3395. 7. Ranganathan S,Walsh ES,Tew KD. Glyoxalase-I in detoxification studies using a glyoxalase-I transfectant cell line. Biochem J 1995;309:127–131. 8. Ranganathan S, Ciaccio PJ,Walsh ES,Tew KD. Genomic sequence of human glyoxalase-I: analysis of promoter activity and its regulation. Gene 1999;240:149–155. 9. Vince R, Daluge S,Wadd WB. Studies on the inhibition of glyoxalase I by S-substituted glutathiones. J Med Chem 1971;14:402–404. 10. Thornalley PJ, Ladan MJ, Ridgeway SJS, Kang Y.Antitumor activity of S-p-promobenzyl) glutathione diesters in vitro: a structure activity study. J Med Chem 1996;39:3409–3411. 11. Kavarana MJ, Kovaleva EG, Creighton DJ,Wollman MB, Eiseman JL. Mechanism-based competitive inhibitors of glyoxalase I: intracellular delivery, in vitro antitumor activities, and stabilities in human serum and mouse serum. J Med Chem 1999;42:221–228. 12. Creighton DJ, Hamilton DS, Kavarana MJ, Sharkey EM, Eiseman JL. Glyoxalase enzyme system as a potential target for antitumor drug development. Drugs of the Future 2000;25:385–392. 13. Morgan AS, Ciaccio PJ,Tew KD, Kauvar LM. Isozyme specific GST inhibitors potentiate drug sensitivity in cultured human tumor cell lines. Cancer Chemother Pharmacol 1996;37: 363–370. 14. Johansson AS, Ridderstrom M, Mannervik B.The human glutathione transferase P1-1 specific inhibitor TER117 designed for overcoming cytostatic-drug resistance is also a strong inhibitor of glyoxalase I. Mol Pharmacol 2000;57:619–624. 15. Sandor V, Fojo T, Bates SE. Future perspectives for the development of P-glycoprotein modulators. Drug Resistance Updates 1998;1:190–200. 16. McLellan LI,Wolf CR. Glutathione and glutathione-dependent enzymes in cancer drug resistance. Drug Resistance Updates 1999;2:153–164. 17. Tew KD, Houghton JA, Houghton PJ. Preclinical and clinical modulation of anticancer drugs. Boca Raton, Florida: CRC Press, 1993.