Doxorubicin-induced apoptosis in caspase-8-deficient neuroblastoma cells is mediated through direct action on mitochondria

A. Rebbaa, P. M. Chou, M. Emran, B. L. Mirkin

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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. Purpose: 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. Methods: 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. Results: 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. Conclusion: These results indicate that the p53/Fas/caspase-8 system does not play a role in mediating the apoptotic action of doxorubicin in the human neuroblastoma cell line SKN-SH. Thus, mitochondria and downstream apoptotic signaling intermediates may be considered as key targets for doxorubicin-induced apoptosis in neuroblastoma tumors having deficiencies in the Fas/caspase-8 system.

Original languageEnglish (US)
Pages (from-to)423-428
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume48
Issue number6
DOIs
StatePublished - 2001

Keywords

  • Apoptosis
  • Caspase-8
  • Doxorubicin
  • Mitochondria
  • Neuroblastoma

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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