Caspase-8 activation independent of CD95/CD95-L interaction during paclitaxel-induced apoptosis in human colon cancer cells (HT29-D4)

Antimicrotubule agent-induced apoptosis was examined in the proliferating h uman colon cancer cell line HT29-D4. G2/M arrest and subsequent apoptosis w ere dose-dependent, both observed with 100 nM paclitaxel or docetaxel and 1 0 nM vinorelbine. Bcl-x(1), phosphorylation was observed simultaneously wit h mitotic block, then caspase-3 cleavage and poly(ADP-ribose) polymerase de gradation were detected 48 hr later. By using both enzymatic assay and immu noblot detection of cleaved fragments, we showed that caspase-8, a central component of the CD95-induced apoptotic pathway, was significantly activate d during paclitaxel exposure, contemporary to apoptosis occurrence. Caspase -8 activation and apoptosis were independent of CD95 ligation and evidenced only for concentrations inducing Bcl-x(L), phosphorylation and a decrease in mitochondria permeability. Similar results were obtained with docetaxel and vinca alkaloids. Thus, antimitotic drugs may induce apoptosis via caspa se-8 activation independently of CD95/CD95-L. Caspase-8 may be a common med iator of anticancer drug-induced apoptosis that could represent a promising target for future therapies. (C) 2000 Elsevier Science Inc.