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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

Effect of curcumin and methylglyoxal (MGO) at the ATP level in tumor cells.Astrocytoma 1321N1 cells (A) and JIMT-1cells (B) were seeded (5000 cells/well) and cultured in the presence of curcumin (0–100 µM) or MGO (0–1000 µM) for 6 h. Cellular ATP content was determined using the CellTiter-Glo® Luminescent Cell Viability Assay. Data represent the mean±S.D. of independent experiments (n = 12).
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pone-0003508-g008: Effect of curcumin and methylglyoxal (MGO) at the ATP level in tumor cells.Astrocytoma 1321N1 cells (A) and JIMT-1cells (B) were seeded (5000 cells/well) and cultured in the presence of curcumin (0–100 µM) or MGO (0–1000 µM) for 6 h. Cellular ATP content was determined using the CellTiter-Glo® Luminescent Cell Viability Assay. Data represent the mean±S.D. of independent experiments (n = 12).

Mentions: It has been shown that MGO affects energy metabolism [24]. If curcumin-induced Glo1 inhibition leads to accumulation of MGO, both of curcumin and MGO are expected to have similar effects at metabolic activity of tumor cells. Therefore, we analyzed the ATP-content of 1321N1 and JIMT-1 cells treated with various concentrations of curcumin and MGO. As shown in figure 8, curcumin decreased cellular ATP in a concentration-dependent manner and MGO disclosed comparable effects.


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)

Effect of curcumin and methylglyoxal (MGO) at the ATP level in tumor cells.Astrocytoma 1321N1 cells (A) and JIMT-1cells (B) were seeded (5000 cells/well) and cultured in the presence of curcumin (0–100 µM) or MGO (0–1000 µM) for 6 h. Cellular ATP content was determined using the CellTiter-Glo® Luminescent Cell Viability Assay. Data represent the mean±S.D. of independent experiments (n = 12).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003508-g008: Effect of curcumin and methylglyoxal (MGO) at the ATP level in tumor cells.Astrocytoma 1321N1 cells (A) and JIMT-1cells (B) were seeded (5000 cells/well) and cultured in the presence of curcumin (0–100 µM) or MGO (0–1000 µM) for 6 h. Cellular ATP content was determined using the CellTiter-Glo® Luminescent Cell Viability Assay. Data represent the mean±S.D. of independent experiments (n = 12).
Mentions: It has been shown that MGO affects energy metabolism [24]. If curcumin-induced Glo1 inhibition leads to accumulation of MGO, both of curcumin and MGO are expected to have similar effects at metabolic activity of tumor cells. Therefore, we analyzed the ATP-content of 1321N1 and JIMT-1 cells treated with various concentrations of curcumin and MGO. As shown in figure 8, curcumin decreased cellular ATP in a concentration-dependent manner and MGO disclosed comparable effects.

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