Glyoxalase enzyme system as a potential target for antitumor drug
                        development

Creighton, Donald J.; Hamilton, Diana S.; Kavarana, Malcolm J.; Eiseman, Julie L.

doi:10.1358/dof.2000.025.04.858665

Cited by 9 publications

(13 citation statements)

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“…The potential for the Glx system to be an effective drug target, taking advantage of the toxic effects of methylglyoxal, is receiving renewed interest, particularly in the area of anticancer agents [41]. Alterations between eukaryotic GlxI enzymes and those from bacterial sources such as E. coli might also be targeted for [42][43][44][45][46].…”

Section: Discussionmentioning

confidence: 99%

Investigation of metal binding and activation of Escherichia coli glyoxalase I: kinetic, thermodynamic and mutagenesis studies

Clugston

Yajima

Honek

2004

Biochemical Journal

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GlxI (glyoxalase I) isomerizes the hemithioacetal formed between glutathione and methylglyoxal. Unlike other GlxI enzymes, Escherichia coli GlxI exhibits no activity with Zn(2+) but maximal activation with Ni(2+). To elucidate further the metal site in E. coli GlxI, several approaches were undertaken. Kinetic studies indicate that the catalytic metal ion affects the k (cat) without significantly affecting the K (m) for the substrate. Inductively coupled plasma analysis and isothermal titration calorimetry confirmed one metal ion bound to the enzyme, including Zn(2+), which produces an inactive enzyme. Isothermal titration calorimetry was utilized to determine the relative binding affinity of GlxI for various bivalent metals. Each metal ion examined bound very tightly to GlxI with an association constant ( K (a))>10(7) M(-1), with the exception of Mn(2+) ( K (a) of the order of 10(6) M(-1)). One of the ligands to the catalytic metal, His(5), was altered to glutamine, a side chain found in the Zn(2+)-active Homo sapiens GlxI. The affinity of the mutant protein for all bivalent metals was drastically decreased. However, low levels of activity were now observed for Zn(2+)-bound GlxI. Although this residue has a marked effect on metal binding and activation, it is not the sole factor determining the differential metal activation between the human and E. coli GlxI enzymes.

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Section: Discussionmentioning

confidence: 99%

Investigation of metal binding and activation of Escherichia coli glyoxalase I: kinetic, thermodynamic and mutagenesis studies

Clugston

Yajima

Honek

2004

Biochemical Journal

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“…Limiting the accumulation of AGEs via enhanced detoxification of MG is an additional metabolic adaptation for cancers exploiting the Warburg effect. This anti-apoptotic defense is primarily accomplished via the upregulation of the glyoxalase system (GLO1/GLO2), which converts MG to d -lactate using glutathione (GSH) as a catalytic co-factor [ 17 ]. GLO1 has been reported to be amplified at the DNA, RNA, or protein level in a variety of primary human cancers and derived cell lines [ 18 , 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models

Jandial

Neman

Lim

et al. 2018

IJMS

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Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S-(p-bromobenzyl) glutathione dicyclopentyl ester (p-BrBzGSH(Cp)2) increased levels of the DNA-AGE N2-1-(carboxyethyl)-2′-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp)2 exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

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“…In the cases of 3b and 3c, selectivity could also arise from the 10-fold lower levels of GlxII activity in L1210 cells compared with splenic lymphocytes, as 3b and 3c are slowly hydrolysed in the presence of the GlxII [14]. Low activity of GlxII is a general characteristic of tumours [27].…”

Section: Antitumour Activities In Vitromentioning

confidence: 99%

Glyoxalase I inhibitors in cancer chemotherapy

Creighton

Zheng

Holewinski

et al. 2003

Biochemical Society Transactions

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Several recent developments suggest that the GSH-dependent glyoxalase enzyme system deserves renewed interest as a potential target for antitumour drug development. This summary focuses on the design and development of new classes of tumoricidal agents that specifically target this elementary detoxification pathway in order to induce elevated concentrations of cytotoxic methylglyoxal in tumour cells. Special emphasis is placed on structure- and mechanism-based inhibitors of GlxI (glyoxalase I), the first enzyme in the pathway. A new class of bivalent transition-state analogues is described that simultaneously bind the active site on each subunit of the homodimeric human GlxI, resulting in K (i) values as low as 1 nM. Also described is a new family of bromoacyl esters of GSH that function as active-site-directed irreversible inhibitors of GlxI. Newer prodrugs for delivering the GSH-based inhibitors into tumour cells include reactive sulphoxide esters that undergo acyl exchange with endogenous GSH to give the inhibitors, and polymethacrylamide esters of the inhibitors that are potentially tumour-selective on the basis of the "enhanced permeability and retention effect". Finally, a preliminary evaluation of the efficacy of selected GlxI inhibitors in tumour-bearing mice is given.

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Glyoxalase enzyme system as a potential target for antitumor drug development

Cited by 9 publications

References 0 publications

Investigation of metal binding and activation of Escherichia coli glyoxalase I: kinetic, thermodynamic and mutagenesis studies

Investigation of metal binding and activation of Escherichia coli glyoxalase I: kinetic, thermodynamic and mutagenesis studies

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models

Glyoxalase I inhibitors in cancer chemotherapy

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