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

Cell Cycle. 2005 Mar;4(3):501-7. doi: 10.4161/cc.4.3.1550. Epub 2005 Mar 18.


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 beta-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 beta-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 beta-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkanes / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Bromodeoxyuridine / pharmacology
  • Carbamates / pharmacology*
  • Cell Line, Tumor
  • Cellular Senescence*
  • Flow Cytometry
  • Gene Expression Regulation*
  • Humans
  • Hydrogen-Ion Concentration
  • Inhibitory Concentration 50
  • Lactones / pharmacology*
  • Microtubules / chemistry
  • Microtubules / drug effects*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitosis
  • Paclitaxel / pharmacology
  • Phenotype
  • Pyrones / pharmacology*
  • Signal Transduction
  • Time Factors


  • Alkanes
  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Carbamates
  • Lactones
  • Pyrones
  • discodermolide
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Bromodeoxyuridine
  • Paclitaxel