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

Autor: Monika Krüger, Gerd Birkenmeier, Martin Buchold, Ulrich Sack, Inge Lindner, Thore Santel, Mookambeswaran A. Vijayalakshmi, Nasr Y. A. Hemdan, Marcus Hollenbach, Gabi Pflug, Rolf Gebhardt, Klaus Huse, Mathias Platzer, Antje Hutschenreuter, Marina Bigl, Thomas S. Weiss, Wolfgang Schellenberger, Claudia Birkemeyer, Marco Groth, Andreas Otto, Angelika Schäfer, Anja Hintersdorf, Ilka Oerlecke
Jazyk: angličtina
Rok vydání: 2008
Předmět:
Lipopolysaccharides
Curcumin
Cell Survival
medicine.medical_treatment
Science
Interleukin-1beta
Immunology/Immunomodulation
Anti-Inflammatory Agents
Drug Evaluation
Preclinical
Biology
Models
Biological
Substrate Specificity
chemistry.chemical_compound
Lactoylglutathione lyase
Phenols
Biochemistry/Protein Chemistry
Neoplasms
medicine
Humans
Propidium iodide
Enzyme Inhibitors
Cells
Cultured
Oncology/Neuro-Oncology
Oncology/Prostate Cancer
Cell Proliferation
Flavonoids
Blood Cells
Multidisciplinary
L-Lactate Dehydrogenase
Cell growth
Methylglyoxal
Lactoylglutathione Lyase
Polyphenols
Cell Biology/Cellular Death and Stress Responses
Glutathione
Antineoplastic Agents
Phytogenic
Cytokine
chemistry
Biochemistry
Oncology/Breast Cancer
biology.protein
Medicine
Myricetin
Biochemistry/Drug Discovery
Research Article
Zdroj: PLoS ONE, Vol 3, Iss 10, p e3508 (2008)
PLoS ONE
ISSN: 1932-6203
Popis: BackgroundGlyoxalases (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 findingsCultures 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/significanceThe 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.
Databáze: OpenAIRE
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