Modulation of arachidonic acid metabolism by curcumin and related  -diketone derivatives: effects on cytosolic phospholipase A2, cyclooxygenases and 5-lipoxygenase

Abstract

Aberrant arachidonic acid metabolism is involved in the inflammatory and carcinogenic processes. In this study, we investigated the effects of curcumin, a naturally occurring chemopreventive agent, and related beta-diketone derivatives on the release of arachidonic acid and its metabolites in the murine macrophage RAW264.7 cells and in HT-29 human colon cancer cells. We also examined their effects on the catalytic activities and protein levels of related enzymes: cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenases (COX) as well as 5-lipoxygenase (5-LOX). At 10 micro M, dibenzoylmethane (DBM), trimethoxydibenzoylmethane (TDM), tetrahydrocurcumin (THC) and curcumin effectively inhibited the release of arachidonic acid and its metabolites in lipopolysaccharide (LPS)-stimulated RAW cells and A23187-stimulated HT-29 cells. Inhibition of phosphorylation of cPLA(2), the activation process of this enzyme, rather than direct inhibition of cPLA(2) activity appears to be involved in the effect of curcumin. All the curcuminoids (10 micro M) potently inhibited the formation of prostaglandin E(2) (PGE(2)) in LPS-stimulated RAW cells. Curcumin (20 micro M) significantly inhibited LPS-induced COX-2 expression; this effect, rather than the catalytic inhibition of COX, may contribute to the decreased PGE(2) formation. Without LPS-stimulation, however, curcumin increased the COX-2 level in the macrophage cells. Studies with isolated ovine COX-1 and COX-2 enzymes showed that the curcuminoids had significantly higher inhibitory effects on the peroxidase activity of COX-1 than that of COX-2. Curcumin and THC potently inhibited the activity of human recombinant 5-LOX, showing estimated IC(50) values of 0.7 and 3 micro M, respectively. The results suggest that curcumin affects arachidonic acid metabolism by blocking the phosphorylation of cPLA(2), decreasing the expression of COX-2 and inhibiting the catalytic activities of 5-LOX. These activities may contribute to the anti-inflammatory and anticarcinogenic actions of curcumin and its analogs.

Inhibitory Activities and Attenuated Expressions of 5-LOX with Red Ginseng in Helicobacter pylori-Infected Gastric Epithelial Cells

“…Ginsenoside Rb1 isolated from red ginseng significantly decreased histamine and leukotriene production in a dosedependent manner during mast cell activation [21] as well as lipopolysaccharide-induced proinflammatory cytokine production [43]. Recently, dietary pigment, curcumin appears to block H pylori-induced NF-κB activation, IL-8 gene expression, the cell scattering response [35], and modulate AA metabolism including PLA 2 , COX, and 5-LOX [44]. In a similar way, we found that red ginseng can also regulate H pylori-induced NF-κB activation and subsequent expression of IL-8 in gastric AGS cells associated with 5-LOX regulation.…”

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

“…These compounds may be regarded as potent and direct 5-LO inhibitors. Similarly, the well-recognized curcumin 52 from Curcuma longa L. [39], [129] and the structurally related gingerols 53 from Zingiber officnialis Roscoe [115], [116] proved to inhibit 5-LO in cell-based and cell-free assays with IC 50 < 1 mM. Interestingly, compared to the prenylated hyperforin 48, the structurally related polyphenols such as erychristagallin 46 [130], or kuraridin 47 [105] possessing lipophilic prenyl residues (that seemingly enhance the potency of flavonoids) are significantly less effective with IC 50 values > 20 mM.…”

“…Interestingly, 5-LO and cPLA 2 share structural (C2 domain) and regulatory properties [activated by Ca 2+ and by phosphorylation by members of the mitogen-activated protein kinase (MAPK) family] [31], [34]. Indeed, many studies revealed that natural compounds (e. g., flavonoids and other polyphenols) leading to suppression of LT formation also act as PLA 2 inhibitors preventing AA release [35], [36], [37], [38], [39], [40]. The anti-inflammatory sesterterpenoid manoalide, for instance, is an irreversible inhibitor of PLA 2 enzymes by covalently modifying lysine residues [41].…”

The role of herbs and spices in cancer prevention

“…Likewise, the LOX pathway produces leukotrienes which, like PGs, are potent causal pain agents. One polyphenol compound, curcumin, inhibited COX-dependent arachidonic acid metabolism by 23%, displayed a strongest inhibitory effect on the peroxidase activity of ovine COX-1 (IC 50 ∼50 μM), and significantly decreased induced COX-2 expression (20 μM), although the underlying mechanism remains poorly understood (68,69). Very low concentrations of salicylic acid found in the blood following ingestion of aspirin (10-30 mg doses) have been shown to suppress COX-2 transcription and are thought to explain epidemiological observations which link aspirin use with reduced risk for colon cancer (70).…”