Apoptosis induced by doxorubicin in neurotumor cells is divorced from drug effects on ceramide accumulation and may involve cell cycle-dependent caspase activation

Sabrina Di Bartolomeo, Federica Di Sano, Mauro Piacentini, Angelo Spinedi

Research output: Contribution to journalArticlepeer-review

Abstract

Doxorubicin (0.5 μg/ml) induced caspase-dependent apoptosis in SH-SY5Y neuroblastoma and CHP-100 neuroepithelioma cells. The apoptotic response started to be evident ~ 15 h after drug administration and, as monitored over a 48-h period, was more pronounced in CHP-100 than in SH-SY5Y cells. In both systems, apoptosis was accompanied by elevation of intracellular ceramide levels. Ceramide accumulation was blocked by the ceramide synthase inhibitor fumonisin B1 (25 μM); this compound, however, did not prevent drug-induced apoptosis. Untreated cells from both lines expressed negligible p53 levels; on the other hand, whereas p53 and p21(Cip1/Waf1) were rapidly up-regulated in doxorubicin-treated SH-SY5Y cells, such a response was not observed in CHP-100 cells. Doxorubicin induced a G2/M phase block in both cell lines, but whereas the G1 phase was markedly depleted in CHP-100 cells, it was substantially retained in SH-SY5Y cells. In the latter system, double G1 and G2/M block largely preceded cell death; however, as apoptosis underwent completion, it selectively targeted late S and G2/M cells. Moreover, apoptosis suppression by caspase inhibition did not result in a recovery of the G1 cell population. These results support the notion that doxorubicin-induced apoptosis and ceramide elevation are divorced events in neuroectodermal tumors and that p53 function is at least dispensable for apoptosis completion. Indeed, as G1 cells appear to be refractory to doxorubicin-induced apoptosis, p53 up-regulation and p21(Cip1/Waf1) expression may provide an unfavorable setting for the apoptotic action of the drug.

Original languageEnglish
Pages (from-to)532-539
Number of pages8
JournalJournal of Neurochemistry
Volume75
Issue number2
DOIs
Publication statusPublished - 2000

Keywords

  • Apoptosis
  • Ceramide
  • Doxorubicin
  • Neurotumors
  • p21(Cip1/Waf1)
  • p53

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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