Different apoptotic pathways activated by daunorubicin in human lymphocytes and fibroblasts

Anticancer drugs have been shown to target diverse intracellular elements in conferring a lethal effect in mammalian cells. Many of these drugs induce a common final death pathway, known as apoptosis or programmed cell death. Daunomycin (also named Daunorubicin) is an anthracycline with antineoplastic properties, particularly useful as an antileukemic agent The anthracyclines act on mammalian cells by multiple mechanisms involving cell-membrane effects, intercalation into DNA, and inhibition of topoisomerase II. Several anthracyclines were reported to induce apoptosis in vitro and in vivo, but the mechanism of this action remains unknown. Ceramide synthesis through ceramide synthase appears to be obligatory for daunorubicin-induced apoptosis since fumonisin Bl, a natural specific inhibitor of ceramide synthase, blocks daunorubicin-induced ceramide elevation and apoptosis. The aim of our work was to comparatively analyse the molecular pathways leading to apoptosis induced by daunomycin in HS27 human fibroblasts. Our results show that daunomycin is able to activate two different apoptotic pathways in these cells: early that involving ceramide synthase wich leads to increased intracellular ceramide levels and secondly the P21/WAFl-mediated pathway, dependently or independently on P53 activity. The use of fumonisinBl together with the results obtained using a P53 negative human cell line (U937) permit us to speculate about the possible occurrence of two different apoptotic mechanisms and their potential cross-talk.