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Curcumin inhibits glyoxalase 1: a possible link to its anti-inflammatory and anti-tumor activity.

Santel T, Pflug G, Hemdan NY, Schäfer A, Hollenbach M, Buchold M, Hintersdorf A, Lindner I, Otto A, Bigl M, Oerlecke I, Hutschenreuther A, Hutschenreuter A, Sack U, Huse K, Groth M, Birkemeyer C, Schellenberger W, Gebhardt R, Platzer M, Weiss T, Vijayalakshmi MA, Krüger M, Birkenmeier G - PLoS ONE (2008)

Bottom Line: Results of enzyme kinetics revealed that curcumin, compared to the polyphenols quercetin, myricetin, kaempferol, luteolin and rutin, elicited a stronger competitive inhibitory effect on Glo1 (K(i) = 5.1+/-1.4 microM).Moreover, whereas curcumin was found to hamper the growth of breast cancer (JIMT-1, MDA-MB-231), prostate cancer PC-3 and brain astrocytoma 1321N1 cells, no effect on growth or vitality of human primary hepatocytes was elucidated.The results described herein provide new insights into curcumin's biological activities as they indicate that inhibition of Glo1 by curcumin may result in non-tolerable levels of MGO and GSH, which, in turn, modulate various metabolic cellular pathways including depletion of cellular ATP and GSH content.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry, University of Leipzig, Leipzig, Germany.

ABSTRACT

Background: Glyoxalases (Glo1 and Glo2) are involved in the glycolytic pathway by detoxifying the reactive methylglyoxal (MGO) into D-lactate in a two-step reaction using glutathione (GSH) as cofactor. Inhibitors of glyoxalases are considered as anti-inflammatory and anti-carcinogenic agents. The recent finding that various polyphenols modulate Glo1 activity has prompted us to assess curcumin's potency as an Glo1 inhibitor.

Methodology/principal findings: Cultures of whole blood cells and tumor cell lines (PC-3, JIM-1, MDA-MD 231 and 1321N1) were set up to investigate the effect of selected polyphenols, including curcumin, on the LPS-induced cytokine production (cytometric bead-based array), cell proliferation (WST-1 assay), cytosolic Glo1 and Glo2 enzymatic activity, apoptosis/necrosis (annexin V-FITC/propidium iodide staining; flow cytometric analysis) as well as GSH and ATP content. Results of enzyme kinetics revealed that curcumin, compared to the polyphenols quercetin, myricetin, kaempferol, luteolin and rutin, elicited a stronger competitive inhibitory effect on Glo1 (K(i) = 5.1+/-1.4 microM). Applying a whole blood assay, IC(50) values of pro-inflammatory cytokine release (TNF-alpha, IL-6, IL-8, IL-1beta) were found to be positively correlated with the K(i)-values of the aforementioned polyphenols. Moreover, whereas curcumin was found to hamper the growth of breast cancer (JIMT-1, MDA-MB-231), prostate cancer PC-3 and brain astrocytoma 1321N1 cells, no effect on growth or vitality of human primary hepatocytes was elucidated. Curcumin decreased D-lactate release by tumor cells, another clue for inhibition of intracellular Glo1.

Conclusions/significance: The results described herein provide new insights into curcumin's biological activities as they indicate that inhibition of Glo1 by curcumin may result in non-tolerable levels of MGO and GSH, which, in turn, modulate various metabolic cellular pathways including depletion of cellular ATP and GSH content. This may account for curcumin's potency as an anti-inflammatory and anti-tumor agent. The findings support the use of curcumin as a potential therapeutic agent.

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Related in: MedlinePlus

Keto-Enol Tautomeric forms of curcumin and transition-state of glutathione (GSH) and methylglyoxal (MGO).(A) (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione. (B) (1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-triene-3-one. (C) Transition-state compound of reaction between GSH and MGO.
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pone-0003508-g010: Keto-Enol Tautomeric forms of curcumin and transition-state of glutathione (GSH) and methylglyoxal (MGO).(A) (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione. (B) (1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-triene-3-one. (C) Transition-state compound of reaction between GSH and MGO.

Mentions: Inhibition of Glo1 by compounds unrelated to GSH has been described recently for flavonoids and indomethacin [22], [49]. Selected from flavonoids, Takasawa et al. [22] proposed that compounds possessing a plane configuration of a ketone and a hydroxy group arranged in a distance of 2.8 A may mimic the enediolate intermediate that yields along the reaction pathway of Glo1 (Fig. 10). As curcumin is endowed with similar structural elements (keto-enol forms), it is conceivable that this pharmacophore directly interacts with the active site of Glo1. Curcumin may exist at equilibrium between the diketo and keto-enol forms; the latter is strongly favored by intramolecular H-bonding. In this line, it has been suggested that these structural elements appear to be important for its anti-tumor activity [50]. Recently, we could evidenced that compounds harboring “dicarbonyl” groups such as ethyl pyruvate possess an anti-inflammatory potency and suppress the expression of immune receptors on human macrophages via targeting human Glo1 [51].


Curcumin inhibits glyoxalase 1: a possible link to its anti-inflammatory and anti-tumor activity.

Santel T, Pflug G, Hemdan NY, Schäfer A, Hollenbach M, Buchold M, Hintersdorf A, Lindner I, Otto A, Bigl M, Oerlecke I, Hutschenreuther A, Hutschenreuter A, Sack U, Huse K, Groth M, Birkemeyer C, Schellenberger W, Gebhardt R, Platzer M, Weiss T, Vijayalakshmi MA, Krüger M, Birkenmeier G - PLoS ONE (2008)

Keto-Enol Tautomeric forms of curcumin and transition-state of glutathione (GSH) and methylglyoxal (MGO).(A) (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione. (B) (1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-triene-3-one. (C) Transition-state compound of reaction between GSH and MGO.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2567432&req=5

pone-0003508-g010: Keto-Enol Tautomeric forms of curcumin and transition-state of glutathione (GSH) and methylglyoxal (MGO).(A) (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione. (B) (1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-triene-3-one. (C) Transition-state compound of reaction between GSH and MGO.
Mentions: Inhibition of Glo1 by compounds unrelated to GSH has been described recently for flavonoids and indomethacin [22], [49]. Selected from flavonoids, Takasawa et al. [22] proposed that compounds possessing a plane configuration of a ketone and a hydroxy group arranged in a distance of 2.8 A may mimic the enediolate intermediate that yields along the reaction pathway of Glo1 (Fig. 10). As curcumin is endowed with similar structural elements (keto-enol forms), it is conceivable that this pharmacophore directly interacts with the active site of Glo1. Curcumin may exist at equilibrium between the diketo and keto-enol forms; the latter is strongly favored by intramolecular H-bonding. In this line, it has been suggested that these structural elements appear to be important for its anti-tumor activity [50]. Recently, we could evidenced that compounds harboring “dicarbonyl” groups such as ethyl pyruvate possess an anti-inflammatory potency and suppress the expression of immune receptors on human macrophages via targeting human Glo1 [51].

Bottom Line: Results of enzyme kinetics revealed that curcumin, compared to the polyphenols quercetin, myricetin, kaempferol, luteolin and rutin, elicited a stronger competitive inhibitory effect on Glo1 (K(i) = 5.1+/-1.4 microM).Moreover, whereas curcumin was found to hamper the growth of breast cancer (JIMT-1, MDA-MB-231), prostate cancer PC-3 and brain astrocytoma 1321N1 cells, no effect on growth or vitality of human primary hepatocytes was elucidated.The results described herein provide new insights into curcumin's biological activities as they indicate that inhibition of Glo1 by curcumin may result in non-tolerable levels of MGO and GSH, which, in turn, modulate various metabolic cellular pathways including depletion of cellular ATP and GSH content.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry, University of Leipzig, Leipzig, Germany.

ABSTRACT

Background: Glyoxalases (Glo1 and Glo2) are involved in the glycolytic pathway by detoxifying the reactive methylglyoxal (MGO) into D-lactate in a two-step reaction using glutathione (GSH) as cofactor. Inhibitors of glyoxalases are considered as anti-inflammatory and anti-carcinogenic agents. The recent finding that various polyphenols modulate Glo1 activity has prompted us to assess curcumin's potency as an Glo1 inhibitor.

Methodology/principal findings: Cultures of whole blood cells and tumor cell lines (PC-3, JIM-1, MDA-MD 231 and 1321N1) were set up to investigate the effect of selected polyphenols, including curcumin, on the LPS-induced cytokine production (cytometric bead-based array), cell proliferation (WST-1 assay), cytosolic Glo1 and Glo2 enzymatic activity, apoptosis/necrosis (annexin V-FITC/propidium iodide staining; flow cytometric analysis) as well as GSH and ATP content. Results of enzyme kinetics revealed that curcumin, compared to the polyphenols quercetin, myricetin, kaempferol, luteolin and rutin, elicited a stronger competitive inhibitory effect on Glo1 (K(i) = 5.1+/-1.4 microM). Applying a whole blood assay, IC(50) values of pro-inflammatory cytokine release (TNF-alpha, IL-6, IL-8, IL-1beta) were found to be positively correlated with the K(i)-values of the aforementioned polyphenols. Moreover, whereas curcumin was found to hamper the growth of breast cancer (JIMT-1, MDA-MB-231), prostate cancer PC-3 and brain astrocytoma 1321N1 cells, no effect on growth or vitality of human primary hepatocytes was elucidated. Curcumin decreased D-lactate release by tumor cells, another clue for inhibition of intracellular Glo1.

Conclusions/significance: The results described herein provide new insights into curcumin's biological activities as they indicate that inhibition of Glo1 by curcumin may result in non-tolerable levels of MGO and GSH, which, in turn, modulate various metabolic cellular pathways including depletion of cellular ATP and GSH content. This may account for curcumin's potency as an anti-inflammatory and anti-tumor agent. The findings support the use of curcumin as a potential therapeutic agent.

Show MeSH
Related in: MedlinePlus