Selective inhibition of mitochondrial respiration and glycolysis in human leukaemic leucocytes by methylglyoxal

Biswas, Swati; Ray, Manju; Misra, Sanjoy; Dutta, D.P; Ray, Somrita

doi:10.1042/bj3230343

Cited by 95 publications

(59 citation statements)

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“…The concentrations of GO/MGO used here are similar to those generally used to evaluate the biological effects of these dicarbonyls (10,11,26,34) and are consistent with those (high micromolar range) found in living systems (35). Moreover, these concentrations are close to those used in vitro to generate AGE content in a physiological range (8,36).…”

Section: Discussionsupporting

confidence: 53%

“…Modification of proteins through derivatization by GO and MGO may induce interaction with specific receptors, such as the RAGE and AGE-R family (9), or directly alter protein functions. For instance, MGO inhibits mitochondrial respiration, membrane ATPases and glyceraldehyde-3-phosphate dehydrogenases (10), and DNA and protein synthesis, thereby inducing growth arrest and cell death (11).…”

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confidence: 99%

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Advanced Glycation End Product Precursors Impair Epidermal Growth Factor Receptor Signaling

et al. 2002

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Formation of advanced glycation end products (AGEs)is considered a potential link between hyperglycemia and chronic diabetic complications, including disturbances in cell signaling. It was hypothesized that AGEs alter cell signaling by interfering with growth factor receptors. Therefore, we studied the effects of two AGE precursors, glyoxal (GO) and methylglyoxal (MGO), on the epidermal growth factor receptor (EGFR) signaling pathway in cultured cells. Both compounds prevented tyrosine autophosphorylation induced by epidermal growth factor (EGF) in a time-and dose-dependent manner as well as phospholipase C␥1 recruitment and subsequent activation of extracellular signal-regulated kinases. AGE precursors inhibit EGF-induced EGFR autophosphorylation and tyrosine kinase activity in cell membranes and in EGFR immunoprecipitates. In addition, AGE precursors strongly inhibited cellular phosphotyrosine phosphatase activities and residual EGFR dephosphorylation. AGE precursors induced the formation of EGFR cross-links, as shown by the cross-reactivity of modified EGFR with an anti-N ⑀ (carboxymethyl) lysine antibody, suggesting that altered EGFR signaling was related to carbonyl-amine reactions on EGFR. Aminoguanidine, an inhibitor of AGE formation, partially prevented the EGFR dysfunction induced by GO and MGO. These data introduce a novel mechanism for impaired cellular homeostasis in situations that lead to increased production of these reactive aldehydes, such as diabetes. Diabetes 51:1535-1542, 2002 T he Maillard reaction comprises the nonenzymatic reaction of reducing sugars with molecules containing an amino group, including proteins, phospholipids, and DNA (1,2). After the reversible formation of a Schiff's base between the reducing sugar and free amino group, this reaction proceeds to form advanced glycation end products (AGEs). Aldehydes such as glyoxal (GO) and methylglyoxal (MGO) are also able to induce AGE formation (3). GO and MGO can be generated during glycation of proteins by glucose (3); during lipid peroxidation (4); from metabolic processes, such as base-catalyzed phosphate elimination of glyceraldehyde 3-phosphate and dihydroxyacetone phosphate; and also during the metabolism of acetone and threonine (5).During chronic complications of diabetes and aging, the levels of AGEs derived from the reaction of GO and MGO with proteins rise in plasma proteins, extracellular matrix, and lens proteins (6 -8). Modification of proteins through derivatization by GO and MGO may induce interaction with specific receptors, such as the RAGE and AGE-R family (9), or directly alter protein functions. For instance, MGO inhibits mitochondrial respiration, membrane ATPases and glyceraldehyde-3-phosphate dehydrogenases (10), and DNA and protein synthesis, thereby inducing growth arrest and cell death (11).Because altered response to growth factor may be implicated in the pathogenesis of diabetic ulcers (12) and vascular diseases associated with diabetes (13), we hypothesized that GO and MGO may modify growth factor recepto...

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Section: Discussionsupporting

confidence: 53%

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confidence: 99%

Advanced Glycation End Product Precursors Impair Epidermal Growth Factor Receptor Signaling

et al. 2002

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“…Despite extensive studies on the role of glycolysis in the generation of MG as a glycating factor, data are scarce on such a modification of just glycolytic enzymes. It was shown that MG inhibits glycolysis in metastatic cells of Ehrlich tumor and leukemic leukocytes by the formation of glycated GAPDH [28,29]. Moreover, in vitro glycation with MG of that enzyme from rabbit muscle and also rabbit muscle lactate dehydrogenase (LDH) induces significant reductions in their catalytic activity in a dose-and time-dependent manner [30,31].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of human muscle-specific enolase by methylglyoxal and irreversible formation of advanced glycation end products

Gamian

Staniszewska

Danielewicz

2009

Journal of Enzyme Inhibition and Medicinal Chemistry

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Methylglyoxal (MG) was studied as an inhibitor and effective glycating factor of human muscle-specific enolase. The inhibition was carried out by the use of a preincubation procedure in the absence of substrate. Experiments were performed in anionic and cationic buffers and showed that inhibition of enolase by methylglyoxal and formation of enolasederived glycation products arose more effectively in slight alkaline conditions and in the presence of inorganic phosphate. Incubation of 15 micromolar solutions of the enzyme with 2 mM, 3.1 mM and 4.34 mM MG in 100 mM phosphate buffer pH 7.4 for 3 h caused the loss a 32%, 55% and 82% of initial specific activity, respectively. The effect of MG on catalytic properties of enolase was investigated. The enzyme changed the K M value for glycolytic substrate 2-phospho-D-glycerate (2-PGA) from 0.2 mM for native enzyme to 0.66 mM in the presence of MG. The affinity of enolase for gluconeogenic substrate phosphoenolpyruvate altered after preincubation with MG in the same manner, but less intensively. MG has no effect on V max and optimal pH values. Incubation of enolase with MG for 0-48 h generated high molecular weight protein derivatives. Advanced glycation end products (AGEs) were resistant to proteolytic degradation by trypsin. Magnesium ions enhanced the enzyme inactivation by MG and facilitated AGEs formation. However, the protection for this inhibition in the presence of 2-PGA as glycolytic substrate was observed and AGEs were less effectively formed under these conditions.

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“…6 The beauty of MG, a normal metabolite, lies in the fact that it kills exclusively cancer cells by inhibition of glycolysis and mitochondrial respiration, leaving no adverse effect on normal cells. 7,8 A detailed pharmacokinetic and toxicological study of MG confirmed that it is apparently devoid of any toxic effect. 9 MG can also activate macrophages 10 via superoxide and nitrite production through the MAPK/NF-κB signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

“…This also supports our previous observation that MG can kill cancer cells by depleting energy production through inhibition of both glycolysis 8,34 and mitochondrial respiration 35,36 of malignant cells without affecting normal cells. 7,35,36 The apoptotic potential of Nano-MG has also been established in this study. HBL-100 cells were shown to be nearly twice more prone to apoptosis when treated with Nano-MG where the amount of MG was 40 times lower than MG in bare form.…”

mentioning

confidence: 99%

Nanofabrication of methylglyoxal with chitosan biopolymer: a potential tool for enhancement of its anticancer effect

Pal

Talukdar

Roy

et al. 2015

IJN

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Purpose The normal metabolite methylglyoxal (MG) specifically kills cancer cells by inhibiting glycolysis and mitochondrial respiration without much adverse effect upon normal cells. Though the anticancer property of MG is well documented, its gradual enzymatic degradation in vivo has prompted interest in developing a nanoparticulate drug delivery system to protect it and also to enhance its efficacy. Materials and methods MG-conjugated chitosan nanoparticles (Nano-MG) were prepared by conjugating the carbonyl group of MG with the amino group of chitosan polymer (Schiff’s base formation). Nano-MG were characterized in detail using the dynamic light scattering method, zeta potential measurement, Fourier transform infrared spectroscopy, and transmission electron microscopic analysis. Amount of MG anchored to Nano-MG, stability of Nano-MG, and in vitro release of MG from Nano-MG were estimated spectrophotometrically. Ehrlich ascites carcinoma (EAC) cells, human breast cancer cell line HBL-100, and lung epithelial adenocarcinoma cell line A549 were used as test systems to compare Nano-MG with bare MG in vitro. Cytotoxicity to EAC cells was evaluated by the trypan blue dye exclusion test, and cell viability of HBL-100 and A549 cells were studied using 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis of HBL-100 cells was assessed by flow cytometry and confocal microscopy. In vivo studies were performed on both EAC cells inoculated and also in sarcoma-180-induced solid tumor-bearing Swiss albino mice to assess the anticancer activity of Nano-MG in comparison to bare MG with varying doses, times, and administrative routes. Results Fourier transform infrared spectroscopy revealed the presence of imine groups in Nano-MG due to conjugation of the amino group of chitosan and carbonyl group of MG with diameters of nanoparticles ranging from 50–100 nm. The zeta potential of Nano-MG was +21 mV and they contained approximately 100 μg of MG in 1 mL of solution. In vitro studies with Nano-MG showed higher cytotoxicity and enhanced rate of apoptosis in the HBL-100 cell line in comparison with bare MG, but no detrimental effect on normal mouse myoblast cell line C2C12 at the concerned doses. Studies with EAC cells also showed increased cell death of nearly 1.5 times. Nano-MG had similar cytotoxic effects on A549 cells. In vivo studies further demonstrated the efficacy of Nano-MG over bare MG and found them to be about 400 times more potent in EAC-bearing mice and nearly 80 times more effective in sarcoma-180-bearing mice. Administration of ascorbic acid and creatine during in vivo treatments augmented the anticancer effect of Nano-MG. Conclusion The results clearly indicate that Nano-MG may constitute a promising tool in anticancer therapeutics in the near future.

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Selective inhibition of mitochondrial respiration and glycolysis in human leukaemic leucocytes by methylglyoxal

Cited by 95 publications

References 16 publications

Advanced Glycation End Product Precursors Impair Epidermal Growth Factor Receptor Signaling

Advanced Glycation End Product Precursors Impair Epidermal Growth Factor Receptor Signaling

Inhibition of human muscle-specific enolase by methylglyoxal and irreversible formation of advanced glycation end products

Nanofabrication of methylglyoxal with chitosan biopolymer: a potential tool for enhancement of its anticancer effect

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Selective inhibition of mitochondrial respiration and glycolysis in human leukaemic leucocytes by methylglyoxal

Cited by 95 publications

References 16 publications

Advanced Glycation End Product Precursors Impair Epidermal Growth Factor Receptor Signaling

Advanced Glycation End Product Precursors Impair Epidermal Growth Factor Receptor Signaling

Inhibition of human muscle-specific enolase by methylglyoxal and irreversible formation of advanced glycation end products

Nanofabrication of methylglyoxal with chitosan biopolymer: a potential tool for enhancement of&nbsp;its anticancer effect

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Nanofabrication of methylglyoxal with chitosan biopolymer: a potential tool for enhancement of its anticancer effect