['The induction of p53 expression and stimulation of the Fas/caspase-8 pathway represent major mechanisms by which cytotoxic drugs induce apoptosis, but in neuroblastomas, the caspase-8 gene is often not expressed.', 'The aim of this study was to determine whether doxorubicin could induce apoptosis in caspase-8-deficient neuroblastoma cells and to define its mechanism of action.', 'The caspase-8-deficient human neuroblastoma cell line, SKN-SH, was incubated with doxorubicin and the apoptotic response, as well as expression of apoptotic molecules in the p53/ Fas/caspase-8 pathway, were determined.', 'SKN-SH cells incubated with doxorubicin readily underwent apoptosis in a concentration-dependent manner. Western blot analyses with specific antibodies demonstrated that both p53 and Fas ligand were endogenously expressed in SKN-SH cells, but their expression was not stimulated by doxorubicin. Fas receptor was not detected in these cells and caspase-8 was totally absent. Electron microscopic analyses of SKN-SH cells treated with doxorubicin revealed pronounced alterations in mitochondrial structure. This treatment also induced the release of cytochrome c from mitochondria and activated the downstream apoptotic intermediate, caspase-3.'] Is doxorubicin-induced apoptosis in caspase-8-deficient neuroblastoma cells mediated through direct action on mitochondria?