X-Message-Number: 25711
Date: Tue, 22 Feb 2005 19:06:57 -0800 (PST)
From: Doug Skrecky <>
Subject: microtubules implicated in cellular senescence

Cell Cycle. 2005 Mar 18;4(3) [Epub ahead of print]
The Microtubule Stabilizing Agent Discodermolide is a Potent Inducer of
Accelerated Cell Senescence.
  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 IC(50)-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.

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