TA-270 [4-Hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone], an Anti-Asthmatic Agent, Inhibits Leukotriene Production Induced by IgE Receptor Stimulation in RBL-2H3 Cells

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 307; no. 2; pp. 583 - 588
• Main Authors: Ishiwara, Mitsuteru, Aoki, Yasuo, Takagaki, Hidetsugu, Ui, Michio, Okajima, Fumikazu
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.11.2003
• Subjects: Animals; Anti-Asthmatic Agents - pharmacology; Arachidonate 5-Lipoxygenase - metabolism; beta-N-Acetylhexosaminidases - metabolism; Calcimycin - pharmacology; Cells, Cultured; Cinnamates - pharmacology; Eosinophils - drug effects; Eosinophils - metabolism; Humans; Ionophores - pharmacology; Leukotrienes - metabolism; Lipoxygenase Inhibitors; Mast Cells - drug effects; Mast Cells - enzymology; Mast Cells - metabolism; Neutrophils - drug effects; Neutrophils - metabolism; Quinolones - pharmacology; Receptors, IgE - physiology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.055145

A novel quinolinone derivative, TA-270 [4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1 H )-quinolinone], has been shown to inhibit antigen-induced asthmatic responses including the early-phase bronchoconstriction in actively sensitized guinea pigs. Here we characterized the action mechanisms of TA-270 in cellular level in vitro. In RBL-2H3 mast cells sensitized with dinitrophenol (DNP)-specific IgE, the antigen exhibited several mast cell functions, including hexosaminidase release as a marker of degranulation, production of tumor necrosis factor-α, and production of immunologically detective leukotrienes. These antigen-induced actions were associated with the activation of several early signaling events, including inositol phosphate production reflecting phospholipase C activation and extracellular signal-regulated kinase activation. When the cells were treated with TA-270, the antigen-induced leukotriene production was almost completely suppressed, but other antigen-induced actions listed above were hardly affected. This drug also failed to affect the antigen-induced phospholipase A 2 activation as evaluated by the total release of arachidonic acid and its metabolites from the cells prelabeled with radioactive arachidonic acid. However, TA-270 clearly changed the arachidonic acid metabolic pathway. It suppressed the accumulation of 5-lipoxygenase products, including leukotrienes, but hardly affected the accumulation of cyclooxygenase products. The inhibitory action of TA-270 on leukotriene production was also observed in human neutrophils and eosinophils. We conclude that TA-270 inhibits 5-lipoxygenase activity and, thereby, suppresses the antigen-induced leukotriene production.