title: Simultaneous Addition of Shikonin and Its Derivatives with Lipopolysaccharide Induces Rapid Macrophage Death.
abstract: Macrophages play pivotal roles in inflammatory responses. Previous studies showed that various natural products exert antiinflammatory effects by regulating macrophage activation. Recent studies have shown that shikonin (SHK) and its derivatives (β-hydroxyisovalerylshikonin, acetylshikonin, and isobutylshikonin), which are 1,4-naphthoquinone pigments extracted from the roots of Lithospermum erythrorhizon, have various pharmacological, including antiinflammatory and antitumor, effects. Even though there have been many studies on the antiinflammatory activities of SHK derivatives, only a few have described their direct effects on macrophages. We investigated the effects of SHK derivatives on lipopolysaccharide (LPS)-treated macrophages. Low doses of SHK derivatives induced significant macrophage cytotoxicity (mouse macrophage-like J774.1/JA-4 cells and mouse peritoneal macrophages) in the presence of LPS. SHK activated caspases-3 and -7, which led to DNA fragmentation, but this cytotoxicity was prevented through a pan-caspase inhibitor in LPS-treated JA-4 cells. Maximal cytotoxic effects were achieved when SHK was added immediately before LPS addition. These results indicate that SHK derivatives induce caspase-dependent apoptotic cell death of LPS-treated macrophages and suggest that SHK acts during an early stage of LPS signaling.
authors.affiliation: Laboratory of Biodefense & Regulation, Osaka University of Pharmaceutical Sciences.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Koike
authors.forename: Makio
authors.initials: M
authors.lastname: Shibano
authors.forename: Hideya
authors.initials: H
authors.lastname: Mori
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kohama
authors.forename: Ko
authors.initials: K
authors.lastname: Fujimori
authors.forename: Fumio
authors.initials: F
authors.lastname: Amano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D053938:DNA Fragmentation; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009285:Naphthoquinones / Q000494:pharmacology*
chemical_list: D008070:Lipopolysaccharides; D009285:Naphthoquinones; C016101:shikonin; D053148:Caspase 3; D053179:Caspase 7