The anticancer drug mithramycin A sensitises tumour cells to apoptosis induced by tumour necrosis factor (TNF)

V. Duverger, A. M. Murphy, D. Sheehan, K. England, T. G. Cotter, I. Hayes, F. J. Murphy

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

In this report we show that mithramycin considerably increases the direct cytotoxic effect of tumour necrosis factor (TNF) on tumour cells in vitro. Sensitisation to TNF-induced apoptosis was prevented by the broad caspase inhibitor zVAD-fmk, whereas overexpression of Bcl-2 had no effect. Mithramycin also potentiated cell death induced by Fas agonistic antibodies. In contrast, mithramycin reduced the percentage of cells undergoing apoptosis due to factor withdrawal. TNF-induced activation of NF-kappaB (NF-κB)-dependent gene expression was not modulated by mithramycin treatment. Concomitantly with the increased sensitivity, the protein level of the short-spliced cFLIP variant was downregulated. These results indicate that mithramycin enhances TNF-induced cell death in an NF-κB-independent manner, and suggest that the Fas-associated death domain protein plays a crucial role in the TNF-sensitising effect of mithramycin.

Original languageBritish English
Pages (from-to)2025-2031
Number of pages7
JournalBritish Journal of Cancer
Volume90
Issue number10
DOIs
StatePublished - 17 May 2004

Keywords

  • Anti-Fas
  • Apoptosis
  • Bcl-2
  • GM-CSF
  • Mithramycin A
  • TNF

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