Epothilone B stabilizes microtubuli of macrophages like taxol without showing taxol-like endotoxin activity.

Abstract

Epothilones are a new class of potential antitumor compounds that were isolated from the myxobacterium Sorangium cellulosum. Epothilones have effects on the cytoskeleton similar to those of the antineoplastic drug Taxol. Both compounds inhibit cell proliferation by stabilizing microtubuli, and they compete for the same binding site. In addition, Taxol displays endotoxin-like properties in that it activates macrophages to synthesize proinflammatory cytokines and nitric oxide. We measured nitric oxide release by IFN-gamma-treated murine macrophages as an indicator of macrophage activation by epothilone B. Although epothilone B showed the expected effects on the microtubuli, there was no indication of macrophage stimulatory activity by epothilone B, nor did epothilone B inhibit lipopolysaccharide-mediated nitric oxide release. We conclude that, unlike Taxol, epothilone-mediated microtubuli stabilization does not trigger endotoxin-signaling pathways. Moreover, because the endotoxin-like activity of Taxol may be the cause of some nonhematological clinical side effects, it is to be expected that such effects may not occur with epothilones.