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Carcinogenesis Advance Access published online on August 10, 2005
Carcinogenesis, doi:10.1093/carcin/bgi208
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received June 13, 2005
Revised July 18, 2005
Accepted August 2, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Modulation of arachidonic acid metabolism and nitric oxide synthesis by garcinol and its derivatives

Jungil Hong 1, Shengmin Sang 1, Hye-Jin Park 1, Seok Joo Kwon 1, Nanjoo Suh 1, Mou-Tuan Huang 1, Chi-Tang Ho 2, 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
2 Department of Food Science, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901

* To whom correspondence should be addressed.
Chung S. Yang, E-mail: csyang{at}rci.rutgers.edu


  Abstract

Garcinol, a polyisoprenylated benzophenone, from the fruit rind of Garcinia spp., has been shown to have anti-inflammatory and anti-carcinogenic activities. To study its mechanism of action, we analyzed the effects of garcinol and its derivatives, including cambogin, garcim-1 and garcim-2, on arachidonic acid metabolism and nitric oxide (NO) synthesis in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages as well as in three intestinal cell lines. We also examined the effect of garcinol on cytosolic phospholipase A2 (cPLA2), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and related upstream signaling. At 1 µM, garcinol and its derivatives, added 1h after LPS stimulation, significantly inhibited the release of arachidonic acid and its metabolites in macrophages; garcinol was most effective, showing >50% inhibition. Similar inhibitory activity was also observed in intestinal cells, HT-29, HCT-116 and IEC-6 cells, showing 40-50% inhibition by 1 µM garcinol. In LPS-stimulated macrophages, garcinol inhibited the phosphorylation of cPLA2 without altering its protein level, and the effect was related to the inhibition of ERK1/2 phosphorylation. Garcinol inhibited NF{kappa}B activation and COX-2 expression only when it was added to the cells before LPS stimulation. Garcinol (1 µM) also significantly decreased iNOS expression and NO release from LPS-stimulated macrophages; this is likely due to inhibiting signal transducer and activator of transcription-1 (STAT-1), an upstream event in the activation of iNOS synthesis. The results suggest that garcinol modulates arachidonic acid metabolism by blocking the phosphorylation of cPLA2 and decreases iNOS protein level by inhibiting STAT-1 activation. These activities may contribute to the anti-inflammatory and anti-carcinogenic actions of garcinol and its derivatives.

Keywords: garcinol; cyclooxygenase; phospholipase A2; inducible nitric oxide synthase; NF{kappa}B; JAK/STAT-1.
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