176
Cancer Chemotherapy, Theoretical Foundations of
5
Manipulating p53 Tumor Suppressor
Activity
As one of the most frequently mutated
genes in human cancer, the p53 tumor
suppressor protein has attracted great
interest from drug discoverers. In normal
cells,
p53
acts
as
a
stress-responsive
transcription factor, becoming activated
in response to, for example, ionizing
radiation,
ultraviolet
light,
and
many
cancer
chemotherapeutic
drugs.
Once
activated, p53 targets genes involved in
limiting
cellular
proliferation,
causing
either cell cycle arrest or apoptosis (Fig. 2).
Its frequent inactivation in cancer has
led to many attempts to identify ways
of reinstating p53 activity, or approaches
that exploit the absence of p53 in tumor
cells. However, though it is an intrinsically
dif±cult task for a small molecule to
reinstate wild-type activity in a mutant
protein, the extensive number of distinct
mutations (over 1700 different mutations
have been reported) that can occur in the
p53 gene provides an additional challenge
to this approach.
Despite these signi±cant obstacles, com-
pounds have been identi±ed that reinstate
certain wild-type functions on mutant p53
protein. These compounds appear to sta-
bilize p53 in a form that allows some
properties of the p53 response to be re-
tained. Relating to this general strategy
is the identi±cation of p53-binding pep-
tides, which similarly stabilize mutant
p53, providing further support for the
idea that the ultimate goal of generating
compounds that reinstate p53 activity may
be achievable.
In another approach that exploits p53
activity, attempts have been made to gen-
erate compounds that block p53 activity. A
potential therapeutic application for such
inhibitors would be in reducing the level of
p53-dependent toxicity in normal healthy
tissues that occurs, for example, upon can-
cer therapy. Pi±thrin
α
, which reduces p53
activity, was identi±ed by high-throughput
screening in a cell-based p53 screen. The
Stress (UV, ionizing,
radiation, hypoxia,
chemotherapeutics)
p53
p53
Cell cycle
arrest/
apoptosis
The p53
response
Fig. 2
The p53 response. In normal cells, p53
can be activated by different types of stress, and
it then acts to transcriptionally induce target
genes that cause cell cycle arrest and apoptosis.
In tumor cells, the activity of p53 is lost through
mutation in the p53 gene, or in upstream
regulators that control p53 activity.
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