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

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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 β-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 µM, 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 µM) potently inhibited the formation of prostaglandin E 2 (PGE 2 ) in LPS-stimulated RAW cells. Curcumin (20 µM) 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 µM, 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.