| 19671757 |
Koeberle A, Northoff H, Werz O: Curcumin blocks prostaglandin E2 biosynthesis through direct inhibition of the microsomal prostaglandin E2 synthase-1. Mol Cancer Ther. 2009 Aug;8(8):2348-55. Epub 2009 Aug 11.
Prostaglandin E (2) (PGE (2)) plays a crucial role in the apparent link between tumor growth and chronic inflammation. Cyclooxygenase (COX)-2 and microsomal PGE (2) synthase-1, which are overexpressed in many cancers, are functionally coupled and thus produce massive PGE (2) in various tumors. Curcumin, a polyphenolic beta-diketone from tumeric with anti-carcinogenic and anti-inflammatory activities, was shown to suppress PGE (2) formation and to block the expression of COX-2 and of microsomal PGE (2) synthase-1. Here, we identified microsomal PGE (2) synthase-1 as a molecular target of curcumin and we show that inhibition of microsomal PGE (2) synthase-1 activity is the predominant mechanism of curcumin to suppress PGE (2) biosynthesis. Curcumin reversibly inhibited the conversion of PGH (2) to PGE (2) by microsomal PGE (2) synthase-1 in microsomes of interleukin-1beta-stimulated A549 lung carcinoma cells with an IC (50) of 0.2 to 0.3 micromol/L. Closely related polyphenols (e.g., resveratrol, coniferyl alcohol, eugenol, rosmarinic acid) failed in this respect, and isolated ovine COX-1 and human recombinant COX-2 were not inhibited by curcumin up to 30 micromol/L. In lipopolysaccharide-stimulated human whole blood, curcumin inhibited COX-2-derived PGE (2) formation from endogenous or from exogenous arachidonic acid, whereas the concomitant formation of COX-2-mediated 6-keto PGF (1) alpha and COX-1-derived 12 (S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid was suppressed only at significant higher concentrations. Based on the key function of PGE (2) in inflammation and carcinogenesis, inhibition of microsomal PGE (2) synthase-1 by curcumin provides a molecular basis for its anticarcinogenic and anti-inflammatory activities. |
1(0,0,0,1) |