Caspase inhibition switches doxorubicin-induced apoptosis to senescence

Abdelhadi Rebbaa*, Xin Zheng, Pauline M. Chou, Bernard L. Mirkin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

151 Scopus citations

Abstract

The inhibition of apoptosis is generally believed to be a major determinant of resistance to chemotherapy. However, recent findings have shown that caspase inhibitors do not protect cancer cells from death by cytotoxic agents, but may switch drug-induced apoptosis to an alternative 'default death'. The primary goals of this study were to determine the major characteristics of the 'default death' and the mechanism by which this switch is activated. For this purpose, we first investigated putative cell death modes induced by doxorubicin. Molecular markers associated with these death modes were utilized to identify the default death resulting from the inhibition of apoptosis. Our findings demonstrated that doxorubicin induced at least three distinct types of cell death, senescence, apoptosis and a type of necrosis, which were concentration dependent. Specific molecular markers such as p21/WAF1, activated caspase-3 and activated Akt were associated with these death modes. The pan-caspase inhibitor (Q-VD-OPH) greatly reduced doxorubicin-induced caspase-3 activation but did not protect cells against drug toxicity. The combination of doxorubicin and Q-VD-OPH caused an increased expression of p21/ WAF1 and senescence -associated -β-galactosidase activity, but did not alter Akt activation. Collectively, these findings suggest that the inhibition of apoptosis may lead to an increased expression of cell cycle inhibitors and cellular senescence.

Original languageEnglish (US)
Pages (from-to)2805-2811
Number of pages7
JournalOncogene
Volume22
Issue number18
DOIs
StatePublished - May 8 2003

Keywords

  • Apoptosis
  • Drug resistance
  • P21/WAF1
  • Senescence

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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