Diverse effects of docetaxel on inducible nitric oxide production in alveolar macrophages

Abstract

Docetaxel is a derivative of paclitaxel (taxol), a diterpine plant compound that was isolated initially from the bark of the western yew tree, Taxus brevifolia, and is currently used as a fundamental drug in the treatment of a variety of solid cancers. The anti-tumor efficacy of paclitaxel has been attributed in part to modulatory effects on the generation of inflammatory mediators, in particular NO, in macrophages and tumor cells. The purpose of this study was to investigate the effects of docetaxel on lipopolysaccharide (LPS)-induced nitric oxide (NO) synthesis in alveolar macrophages isolated from rats. LPS-induced NO production and inducible NO synthase (iNOS) expression were significantly enhanced in the macrophages isolated from rats injected intraperitoneally with docetaxel (4mg/kg body weight per day for 5 consecutive days) compared with those in macrophages from control rats (vehicle administration). In vivo administration of docetaxel augmented LPS-induced p38 activation but not extracellular signal-related kinase (ERK) activation in isolated macrophages. By contrast, in vitro treatment of macrophages with docetaxel (5 and 10 microg/ml) inhibited LPS-induced NO production and iNOS expression. Thus, in vitro effects of docetaxel on NO generation of macrophages do not explain its in vivo effects. Release of lactate dehydrogenase (LDH) from macrophages was neither affected by in vitro treatment with docetaxel (up to 10 microg/ml) nor by its in vivo administration. These results suggest that docetaxel exerts diverse actions on LPS-induced iNOS expression in alveolar macrophages. We suggest that the in vivo action of docetaxel is mediated by stimulation of p38 activity.