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Carcinogenesis Advance Access published online on April 8, 2004
Carcinogenesis, doi:10.1093/carcin/bgh165
© 2004 by Oxford University Press
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© 2004 Oxford University Press

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

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

Jungil Hong 1, Mousumi Bose 1, Jihyeung Ju 1, Jae-Ha Ryu 1, Xiaoxin Chen 1, Shengmin Sang 1, Mao-Jung Lee 1, and Chung S. Yang 1*

1 Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854

* Corresponding author. E-mail: csyang{at}rci.rutger.edu.

Received 14 January 2004 ; revised 23 March 2004 ; accepted 3 April 2004

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 A2 (cPLA2), 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 cPLA2, the activation process of this enzyme, rather than direct inhibition of cPLA2 activity appears to be involved in the effect of curcumin. All the curcuminoids (10 µM) potently inhibited the formation of prostaglandin E2 (PGE2) in LPS-stimulated RAW cells. Curcumin (20 µM) significantly inhibited LPS-induced COX-2 expression; this effect, rather than catalytic inhibition of COX, may contribute to the decreased PGE2 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 IC50 values of 0.7 and 3 µM, respectively. The results suggest that curcumin affects arachidonic acid metabolism by blocking the phosphorylation of cPLA2, decreasing the expression of COX-2, and inhibiting the catalytic activities of 5-LOX. These activities may contribute to the anti-inflammatory and anti-carcinogenic actions of curcumin and its analogues.

curcumin, {beta}-diketone, cyclooxygenase, 5-lipoxygenase, phospholipase A2, arachidonic acid
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