The microtubule stabilizing agent discodermolide is a potent inducer of accelerated cell senescence

Laura E. Klein, B. Scott Freeze, Amos B. Smith, Susan Band Horwitz

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

Discodermolide is a microtubule stabilizing agent that suppresses dynamic instability and blocks cells in mitosis. Selection of A549 nonsmall cell lung carcinoma cells with increasing concentrations of discodermolide yielded a clone that proliferated in 8 nM. When these cells were exposed to any concentration greater than 8 nM, replication ceased and the cells developed a flattened, enlarged, granular morphology. Accelerated senescence was demonstrated by a functional β-galactosidase activity at pH 6. When parental A549 cells were treated with IC50-concentrations of doxorubicin, Taxol or discodermolide, the latter two drugs quickly produced aberrant mitosis. However, discodermolide, but not Taxol, also produced a large increase in senescence-associated β-galactosidase activity and altered levels of known senescence markers. Although some of these differences between Taxol and discodermolide were dose dependent, only discodermolide produced a doxorubicin-like induction of a senescence phenotype, including a senescence-associated β-galactosidase activity, up-regulation of PAI-1 and p66Shc, and a strong, sustained, Erk1/2 activation. This research provides insights into the mechanism of action of discodermolide and provides the first demonstration of a microtubule stabilizing agent that inhibits tumor cell growth with a powerful induction of accelerated senescence.

Original languageEnglish (US)
Pages (from-to)501-507
Number of pages7
JournalCell Cycle
Volume4
Issue number3
DOIs
StatePublished - Mar 2005

Keywords

  • Accelerated senescence
  • Apoptosis
  • Discodermolide
  • Mitotic catastrophe
  • Taxol®

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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