Neuroblastoma is the most common extracranial solid tumor of childhood. N-type 
neuroblastoma cells (represented by SH-SY5Y and IMR32 cell lines) are 
characterized by a neuronal phenotype. N-type cell lines are generally N-myc 
amplified, express the anti-apoptotic protein Bcl-2, and do not express 
caspase-8. The present study was designed to determine the mechanism by which 
N-type cells die in response to specific cytotoxic agents (such as cisplatin and 
doxorubicin) commonly used to treat this disease. We found that N-type cells 
were equally sensitive to cisplatin and doxorubicin. Yet death induced by 
cisplatin was inhibited by the nonselective caspase inhibitor 
z-Val-Ala-Asp-fluoromethylketone or the specific caspase-9 inhibitor 
N-acetyl-Leu-Glu-His-Asp-aldehyde, whereas in contrast, caspase inhibition did 
not prevent doxorubicin-induced death. Neither the reactive oxygen species nor 
the mitochondrial permeability transition appears to play an important role in 
this process. Doxorubicin induced NF-kappa B transcriptional activation in 
association with I-kappa B alpha degradation prior to loss of cell viability. 
Surprisingly, the antioxidant and NF-kappa B inhibitor pyrrolidine 
dithiocarbamate blocked doxorubicin-induced NF-kappa B transcriptional 
activation and provided profound protection against doxorubicin killing. 
Moreover, SH-SY5Y cells expressing a super-repressor form of I-kappa B were 
completely resistant to doxorubicin killing. Together these findings show that 
NF-kappa B activation mediates doxorubicin-induced cell death without evidence 
of caspase function and suggest that cisplatin and doxorubicin engage different 
death pathways to kill neuroblastoma cells.