Modulation of arachidonic acid metabolism and nitric oxide synthesis by garcinol and its derivatives.
Jungil Hong, Shengmin Sang, Hye-Jin Park, Seok Joo Kwon, Nanjoo Suh, Mou-Tuan Huang, Chi-Tang Ho, Chung S Yang
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020, USA.
Carcinogenesis 2006 Feb
Garcinol, a polyisoprenylated benzophenone, from the fruit rind of Garcinia spp., has been shown to have anti-inflammatory and anticarcinogenic 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 NO synthase (iNOS), and related upstream signaling. At 1 microM, garcinol and its derivatives, added 1 h after LPS stimulation, significantly inhibited the release of arachidonic acid and its metabolites in macrophages; garcinol was the 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 microM 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 NFkappaB activation and COX-2 expression only when it was added to the cells before LPS stimulation. Garcinol (1 microM) also significantly decreased iNOS expression and NO release from LPS-stimulated macrophages; this is probably due to the inhibition of the 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 anticarcinogenic actions of garcinol and its derivatives.
Citation
Jungil Hong, Shengmin Sang, Hye-Jin Park, Seok Joo Kwon, Nanjoo Suh, Mou-Tuan Huang, Chi-Tang Ho, Chung S Yang. Modulation of arachidonic acid metabolism and nitric oxide synthesis by garcinol and its derivatives. Carcinogenesis. 2006 Feb;27(2): 278-86
PMID: 16093250
View Full Text