Benzoxathiole derivative blocks lipopolysaccharide-induced nuclear factor-κB activation and nuclear factor-κB-regulated gene transcription through inactivating inhibitory κB kinase β

Hak Kim Byung, Eunmiri Roh, Young Lee Hwa, In Jeong Lee, Byeongwoo Ahn, Sang Hun Jung, Heesoon Lee, Sang Bae Han, Youngsoo Kim

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Benzoxathiole derivatives have been used in the treatment of acne and have shown cytostatic, antipsoriatic, and antibacterial properties. However, little is known about the molecular basis for these pharmacological properties, although nuclear factor (NF)-κB activation is closely linked to inflammation and cell proliferation. Here, we demonstrate that the novel small-molecule benzoxathiole 6,6-dimethyl-2-(phenylimino)-6,7-dihydro-5H-benzo- [1,3]oxathiol-4-one (BOT-64) inhibits NF-κB activation with an IC 50 value of 1 μM by blocking inhibitory κB (IκB) kinase β (IKKβ), and suppresses NF-κB-regulated expression of inflammatory genes in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. BOT-64 inhibits IKKβ-mediated IκBα phosphorylation in LPS-activated macrophages, resulting in sequential prevention of downstream events, including proteolytic degradation of IκBα, DNA binding ability, and transcriptional activity of NF-κB. BOT-64 inhibits LPS-inducible IKKβ activity in the cells and catalytic activity of highly purified IKKβ. Moreover, the effect of BOT-64 on cell-free IKKβ was abolished by substitution of Ser-177 and Ser-181 residues in the activation loop of IKKβ to glutamic acid residues, indicating a direct interaction site of benzoxathiole. BOT-64 attenuates NF-κB-regulated expression of inflammatory genes such as inducible nitric-oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in LPS-activated or expression vector IKKβ-transfected macrophages. Furthermore, BOT-64 dose-dependently increases the survival rates of endotoxin LPS-shocked mice.

Original languageEnglish (US)
Pages (from-to)1309-1318
Number of pages10
JournalMolecular Pharmacology
Volume73
Issue number4
DOIs
StatePublished - Apr 1 2008
Externally publishedYes

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