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SEVERAL NOVEL ANTI CANCER STRATEGIES ARE AIMED AT
ACTIVATING/ REACTIVATING WILD TYPE OR MUTANT p53
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Introduction:
p53 prevents cancer formation by suppressing a tumour and also plays a role in
preventing genome mutation by maintaining a stability, also a role in apoptosis and
inhibition of angiogenesis and hence is known as “the guardian of the genome”
...
In about 50% of human cancers, mutational
inactivation of p53 is the most common event found
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In tumour suppression p53
plays a role by blocking angiogenesis, inducing growth arrest, senescence and apoptosis
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Hence, p53 is
very important in the anti-cancer drugs research
...
p53 reacts to various cellular stresses which involves oncogene
activation, genotoxic damages and hypoxia
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Here we will discuss the various anti-cancer strategies:
1) Targeting wild type p53 – To Activate
2) Targeting Mutant p53 - To Reactivate
3) Targeting p53 Regulators - To Activate p53

1) Targeting wild type p53 – To Activate:
This strategy will includes the use of:
- Chemoradiation which activates endogenous wild type p53,
- Gene therapy to introduce wild type p53 or modified adenovirus to kill cancer cells
with mutant p53
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Chemoradiation:
In anticancer therapies, chemoradiation targets p53 to activate and stabilize it by
causing a major DNA damage
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And the further study of these responses of p53 will help in further improvement of the
effectiveness of the anticancer strategies
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The
use of virus to deliver wild type p53 is one of the most commonly used gene therapy
technique, where the tumour growth is inhibited by delivering the wild type p53 in the
cancer cell using retrovirus mediated genes
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To eliminate mutant p53 containing cancer cells by adenovirus: ONYX-015 shows an
anticancer activity, it uses E1B-deleted adenovirus for p53 related gene therapy, where
it activates the wild type p53 by suppressing the cancer cells by selectively reproducing
a wild type p53-deficient cells
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e
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It was recognized by a cell proliferation assay using an isogenic
cancer cell lines that vary in their p53 status
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As it
causes cancellation of cancer cell survival and oncogenic pathway, it can be used in a
novel anticancer therapy
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Also the functions of p53 can be restored by proper folding
of the unfolded p53 using certain small molecules or peptides
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It restores the transcription activity of mutant p53 to
transactivate p53 targeted genes and also induces gathering of wild type p53 to
sensitize the cancer cells to the radiation
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These derivatives are known to rescue
mutant p53 functions, inducing growth inhibition, apoptosis and suppression of growth
of tumour
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e
...
e
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These compounds restores
the sequence specific DNA binding and leads to transactivation of p53 when mutant p53
conformation is changed to wild type p53
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Ellipticine: Ellipticine reactivates p53 by increasing the transcription of p21 and causes
arrest of G1 phase and it also restores the sequence-specific DNA binding which causes
transactivation of p53
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And it is an active metabolite of the cytoprotector amifostine
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Also, Mdm2 inhibition reactivates p53
and boost cell killing
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b) Mdm2 promotes p53 degradation by acting as an E3 ubiquitin ligase
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These compounds include Nutlins, Benzodiazepinediones
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It also reveals a direct antiangiogenic and antiosteoclastic activity
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Mdm2 ubiquitin ligase inhibitors:
HLI98: HLI98 reactivates p53 and was detected on a cell-based screening using an Mdm2
autoubiquitination assay, where they stabilize p53 and Mdm2 to induce transcription
and apoptosis
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These
compounds are the nongenotoxic agents which do not cause any DNA damage
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Further as we go on gaining
the better knowledge of p53, it will be more helpful in the novel anticancer strategies
and its further research on targeting p53 signalling pathway
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The
transactivation
domain (TD) and
proline-rich
domain (PD) that
are situated at
the N-terminus, the DNA binding and mutation hot spots domain at the central of
the molecule, whereas the oligomerization domain (OD) and regulatory domain
(RD) at the C-terminus
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As shown in the
figure, 3 classes of p53 targeting compounds are recognized and characterized
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The second class of
compounds reactivates and rescues the mutant p53 with an application in
cancers carrying a p53 mutation
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Reference:
1
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The hallmarks of cancer
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[PubMed]
2
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Targeting p53 for Novel Anticancer Therapy
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Vazquez A, Bond EE, Levine AJ, Bond GL
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Nat Rev Drug Discov
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[PubMed]
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Mdm2 promotes the rapid degradation of
p53
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p53 as a target for anticancer drug development
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13
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ubiquitin ligase activity stabilize and activate p53 in cells
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