Acacetin suppressed LPS-induced up-expression of iNOS and COX-2 in murine macrophages and TPA-induced tumor promotion in mice
Journal
Biochemical Pharmacology
Journal Volume
72
Journal Issue
10
Pages
1293-1303
Date Issued
2006
Author(s)
Abstract
Acacetin (5,7-dihydroxy-4′-methoxyflavone), a flavonoid compound, has anti-peroxidative and anti-inflammatory effects. In this study, we investigated the inhibitory effects of acacetin and a related compound, wogonin, on the induction of NO synthase (NOS) and COX-2 in RAW 264.7 cells activated with lipopolysaccharide (LPS). Acacetin markedly and actively inhibited the transcriptional activation of iNOS and COX-2. Western blotting, reverse transcription-polymerase chain reaction (PCR), and real-time PCR analyses demonstrated that acacetin significantly blocked protein and mRNA expression of iNOS and COX-2 in LPS-inducted macrophages. Treatment with acacetin reduced translocation of nuclear factor-κB (NFκB) subunit and the dependent transcriptional activity of NFκB. The activation of NFκB was inhibited by prevention of the degradation of inhibitor κB (IκB). Furthermore, acacetin inhibited LPS-induced phosphorylation as well as degradation of IκBα. We further investigated the roles of tyrosine kinase, phosphatidylinositiol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) in LPS-induced macrophages. We found that acacetin also inhibited LPS-induced activation of PI3K/Akt and p44/42, but not p38 MAPK. After initiation of 7,12-dimethlybene[a]anthracene (DMBA), applying acacentin topically before each 12-O-tetradecanoylphorbol 13-acetat (TPA) treatment was found to reduce the number of papillomas at 20 weeks. Taken together, these results show that acacetin down regulates inflammatory iNOS and COX-2 gene expression in macrophages by inhibiting the activation of NFκB by interfering with the activation PI3K/Akt/IKK and MAPK, suggesting that acacetin is a functionally novel agent capable of preventing inflammation-associated tumorigenesis. © 2006 Elsevier Inc. All rights reserved.
Type
journal article