Doxorubicin-induced death in neuroblastoma does not involve death receptors in S-type cells and is caspase-independent in N-type cells

Oncogene. 2002 Sep 5;21(39):6132-7. doi: 10.1038/sj.onc.1205879.


Death induced by doxorubicin (dox) in neuroblastoma (NB) cells was originally thought to occur via the Fas pathway, however since studies suggest that caspase-8 expression is silenced in most high stage NB tumors, it is more probable that dox-induced death occurs via a different mechanism. Caspase-8 silenced N-type invasive NB cell lines LAN-1 and IMR-32 were investigated for their sensitivity to dox, and compared to S-type noninvasive SH-EP NB cells expressing caspase-8. All cell lines had similar sensitivities to dox, independently of caspase-8 expression. Dox induced caspase-3, -7, -8 and -9 and Bid cleavage in S-type cells and death was blocked by caspase inhibitors but not by oxygen radical scavenger BHA. In contrast, dox-induced death in N-type cells was caspase-independent and was inhibited by BHA. Dox induced a drop in mitochondrial membrane permeability in all cell lines. Dox-induced death in S-type cells gave rise to apoptotic nuclei, whereas in N-type cells nuclei were non-apoptotic in morphology. Transfection of SH-EP cells with a dominant negative FADD mutant inhibited TRAIL-induced death, but had no effect on dox-induced apoptosis. These results suggest that S-type cells undergo apoptosis after dox treatment independently of death receptors, whereas N-type cells are killed by a caspase-independent mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Antineoplastic Agents / pharmacology*
  • Antioxidants / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins
  • Butylated Hydroxyanisole / pharmacology
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology
  • Carrier Proteins / metabolism*
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Cell Nucleus / metabolism
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm / physiology
  • Enzyme Inhibitors / pharmacology
  • Fas-Associated Death Domain Protein
  • Genes, Dominant
  • Humans
  • Membrane Glycoproteins / pharmacology
  • Neoplasm Invasiveness / physiopathology
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology
  • Reactive Oxygen Species
  • TNF-Related Apoptosis-Inducing Ligand
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Antioxidants
  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Membrane Glycoproteins
  • Reactive Oxygen Species
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • Butylated Hydroxyanisole
  • Doxorubicin
  • Caspases