Abstract
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 (Ki = 5.1±1.4 µM). Applying a whole blood assay, IC50 values of pro-inflammatory cytokine release (TNF-α, IL-6, IL-8, IL-1β) were found to be positively correlated with the Ki-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.
Highlights
Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene3,5-dione) is a polyphenol derived from the plant Curcuma longa
We found that curcumin acts as a strong inhibitor of Glo1, causes depletion of cellular ATP and GSH and has a potential impact at cellular metabolism predominantly in cells whose energy gain relies on the glycolytic pathway
Upon addition of curcumin and other selected flavonoids at increasing concentrations to the cultured cells, we observed a strong suppression of the pro-inflammatory cytokine release as exemplified by IL-1b (Fig. 2)
Summary
Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene3,5-dione) is a polyphenol derived from the plant Curcuma longa. In various animal models, curcumin was found to suppress symptoms associated with type II diabetes [3] rheumatoid arthritis [4], Alzheimer disease [5], promoted wound healing [6] and was protective in an animal model of sepsis [7]. These effects seem to be linked to the anti-inflammatory effect of curcumin that, in turn, may be attributed to its ability to inhibit cyclooxygenase-2, lipoxygenase and inducible nitric oxide synthase (iNOS) [8]. The recent finding that various polyphenols modulate Glo activity has prompted us to assess curcumin’s potency as an Glo inhibitor
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
