Curcumin Inhibits Glyoxalase 1—A Possible Link to Its Anti-Inflammatory and Anti-Tumor Activity

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.

HMGB1, S100 proteins and other RAGE ligands in cancer - markers, mediators and putative therapeutic targets

“…The activity of glyoxalase I may be modulated by various polyphenols, e.g. curcumin is a strong competitive inhibitor of glyoxalase I with concomitant antiinflammatory activity 34 . Curcumin was shown to inhibit the growth of breast and prostate cancer and brain astrocytoma and could be a promising anticancer compound.…”

Glyoxalases in Urological Malignancies

“…In 2002 it was demonstrated a sensitized cytotoxic effect of BCNU with ß -glucan in PC3 PCa cells, which was associated with a drastic (approximately 80%) inactivation of Glo1 [63]. More recently, it has been also reported that curcumin inhibits Glo1 with the consequent intracellular accumulation of non-tolerable levels of MG and GSH, that, by modulating various metabolic cellular pathways, hamper malignant cells growth [64]. Finally, more recently, Baunacke et al [53] identified ethyl pyruvate as agent targeting Glo1 and defanging some malignancy-associated properties of PCa cells and Valenti et al [65] found that 3-bromopyruvate induced rapid human PCa cell death by affecting, among the others, Glo1.…”

“…Hence, in PCa, utilization of specific inhibitors of Glo1 might indeed serve as an effective anticancer strategy. Several natural compounds have been proposed as Glo1 inhibitors attenuating the growth of PCa [53,[62][63][64][65].…”

Design, Synthesis and Biological Evaluation of Potent Human Glyoxalase I Inhibitors

“…[4][5][6][7][8][9][10][11][12][13][14][15][16] One of the most employed compounds that are derivatives of S-(N-aryl-N-hydroxycarbamoyl) glutathione originally prepared by Creighton and colleagues. [4][5][6][7][8] For example, compounds 1-3 are good inhibitors of human GLO1 (hGLO1), with reported comparable K i value of 46, 10, and 14 nM, respectively (Fig.…”

“…To our delight, compound 4 exhibited K i value of 8 nM against hGLO1, which is determined by us recently. Some other important natural products have also been widely utilized as a hGLO1 inhibitor, such as delphinidin, 9) anthocyanidin, 9) methyl gerfelin (M-GFN), 10) curcumin, 11) and flavonoides.…”