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gamma-Mangostin Inhibits inhibitor-kappaB Kinase Activity and Decreases Lipopolysaccharide-Induced cyclooxygenase-2 Gene Expression in C6 Rat Glioma Cells

gamma-Mangostin Inhibits inhibitor-kappaB Kinase Activity and Decreases Lipopolysaccharide-Induced cyclooxygenase-2 Gene Expression in C6 Rat Glioma Cells

Keigo Nakatani, Tohru Yamakuni, Nobuhiko Kondo, Tsutomu Arakawa, Kenji Oosawa, Susumu Shimura, Hiroyasu Inoue, Yasushi Ohizumi

Mol Pharmacol. 2004 Sep;66(3):667-74.

PMID: 15322259

Abstract:

We investigated the effect of gamma-mangostin purified from the fruit hull of the medicinal plant Garcinia mangostana on spontaneous prostaglandin E(2) (PGE(2)) genase release and inducible cyclooxy-2 (COX-2) gene expression in C6 rat glioma cells. An 18-h treatment with gamma-mangostin potently inhibited spontaneous PGE(2) release in a concentration-dependent manner with the IC(50) value of approximately 2 microM, without affecting the cell viability even at 30 microM. By immunoblotting and reverse-transcription polymerase chain reaction, we showed that gamma-mangostin concentration-dependently inhibited lipopolysaccharide (LPS)-induced expression of COX-2 protein and its mRNA, but not those of constitutive COX-1 cyclooxygenase. Because LPS is known to stimulate inhibitor kappaB (IkappaB) kinase (IKK)-mediated phosphorylation of IkappaB followed by its degradation, which in turn induces nuclear factor (NF)-kappaB nuclear translocation leading to transcriptional activation of COX-2 gene, the effect of gamma-mangostin on the IKK/IkappaB cascade controlling the NF-kappaB activation was examined. An in vitro IKK assay using IKK protein immunoprecipitated from C6 cell extract showed that this compound inhibited IKK activity in a concentration-dependent manner, with the IC(50) value of approximately 10 microM. Consistently gamma-mangostin was also observed to decrease the LPS-induced IkappaB degradation and phosphorylation in a concentration-dependent manner, as assayed by immunoblotting. Furthermore, luciferase reporter assays showed that gamma-mangostin reduced the LPS-inducible activation of NF-kappaB-and human COX-2 gene promoter region-dependent transcription. gamma-Mangostin also inhibited rat carrageenan-induced paw edema. These results suggest that gamma-mangostin directly inhibits IKK activity and thereby prevents COX-2 gene transcription, an NF-kappaB target gene, probably to decrease the inflammatory agent-stimulated PGE(2) production in vivo, and is a new useful lead compound for anti-inflammatory drug development.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP31271075	gamma-Mangostin		31271-07-5	Price

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