The relationship between p53 and chemotherapy is complex. p53 can induce cell death and cell cycle arrest in response to chemotherapy, but the balance of these effects and the specific chemotherapy agent used impacts outcomes. Tumors with wildtype p53 may experience cell cycle arrest, protecting tumor cells, while p53-deficient tumors are more sensitive to chemotherapy due to a lack of DNA damage response. The p53 status of the tumor microenvironment also influences chemotherapy response.
2. p53 and chemotherapy
1.Introduction
1.Introduction
2. Relationship between p53 and chemotherapy
2. Relationship between p53 and chemotherapy
3. Summary
3. Summary
3. p53
p53
Introduction
Introduction
Regulation
Regulation
History
History
Introduction
Activation
Activation
Function
Function
4. p53 introduction
• A 53 kD nuclear phosphoprotein
• Encoded by TP53 gene
• Short arm of chromosome 17
• Regulates cell growth and proliferation
• Prevents unrestrained cell division after
chromosomal damage
• The absence of p53 increases the risk of developing
cancers
10. Regulation
• Phosphorylation of N-terminal domain
• Protein kinases targeting p53 More
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MAPK family (JNK1-3, ERK1-2, p38 MAPK)
ATR, ATM, CHK1 and CHK2, DNA-PK, CAK
Oncogenes p14ARF
• Mdm2 More
More
13. p53 and chemotherapy
1.Introduction
1.Introduction
2. Relationship between p53 and chemotherapy
2. Relationship between p53 and chemotherapy
3. Summary
3. Summary
15. Controversy
Relationship between p53 and chemotherapy
Pros • p53 is favourable to chemotherapy
More
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Cons • p53 is unfavourable to chemotherapy
More
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Neutral • p53 is irrelevant with chemotherapy
More
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16. p53 is favourable to chemotherapy
Yamasaki M, et al. Ann Surg Oncol 2010, 17, 634-42
17. p53 is favourable to chemotherapy
Patients with mutations in
p53 showed significantly
poorer prognosis than
those without mutant p53.
p53 IHC staining did not
correlate with prognosis.
Back
Back
18. p53 is unfavourable to chemotherapy
TP53 status was strongly associated with response
Bertheau P, et al. PLoS Med 2007, 4, 585-92
19. p53 is unfavourable to chemotherapy
·TP53-mutant patients have a more favorable event-free survival
· Patients with wild-type TP53 tumors had favorable overall survival, despite the
lack of complete response.
· Patients with TP53-mutant tumors who did not reach complete response had a
significantly shorter overall survival Back
Back
20. p53 is irrelevant with chemotherapy
· p53 protein
overexpression is a
significant marker of
p53 IHC results p53 IHC results,
prognosis (B) observation
· Patients with p53
positive tumors deri-
ved significant
benefit from chemo-
therapy(C).
· Patients with p53
negative tumors had
no survival benefit
p53 IHC positive p53 IHC negative
from chemotherapy
(D).
Tsao MS, et al. J Clin Oncol 2007, 25,5240-7
21. p53 is irrelevant with chemotherapy
· p53 mutation was
not prognostic for
survival in the ob-
servation arm(B)
· Patients with p53 p53 mutation results, observation
mutations did not
derive significant
survival benefit
from chemotherapy
(C).
· Chemotherapy
significantly
prolonged survival
in patients with wild mutant p53 wild-type p53
type p53
compared with
observation (D),
Back
Back
Tsao MS, et al. J Clin Oncol 2007, 25,5240-7
23. p53 and chemotherapy
Induce cell
death in response
Induce early cell to drug-induced
cycle arrest, DNA damages
protecting tumor
cells from
further damages
More
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More
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24. Cyclophosphamide Inhibits Tumor
Proliferation and Stimulates Apoptosis In
Vivo
· In response to CPM, Ki-
67 labeling decreased
dramatically even by 24
hours (C).
· Control tumors had
negligible staining for the
apoptosis marker cleaved
caspase-3 (D),
· High levels of cleaved
caspase-3 were observed
3 and 6 hours after
treatment with CPM (E F )
· A wave of apoptosis
throughout the tumor was
demonstrated at low
power (H–J ), with
maximal
staining visible at 6 hours
after treatment
Chesler L ,et al. Neoplasia 2008, 10, 1268-74
25. Apoptosis in Tumors Treated with Cytotoxic
Chemotherapy Is Driven by p53
· Activation of the p53
pathway and caspase-3
cleavage were minimal in
vehicle-treated tumors,
consistent with the low-level
caspase-3 staining
· Rapid induction of p53 was
observed at 3 hours after
treatment with CPM, with a
peak at 6 hours after
treatment
· Cleaved caspase-3 and -9
were maximal at 6 hours after
treatment and were sustained
during a 12-hour period.
Chesler L ,et al. Neoplasia 2008, 10, 1268-74
26. CPM Treatment of Murine Neuroblastoma
Activates Apoptosis
· Bax, a downstream target of PUMA
and a critical effector of myc-
induced mitochondrial apoptosis,
was strongly expressed and PARP
occurred concurrently, indicating
high levels of apoptosis.
· The proapoptotic effect of CPM
proceeds through the intrinsic p53
regulatory pathway of BH3 proteins,
implicating PUMA, Bax, and Bim as
key effectors of p53 function in
primary murine neuroblastoma
tumors.
Chesler L ,et al. Neoplasia 2008, 10, 1268-74
27. Conclusion
• The p53 pathway plays a significant role in
opposing MYCN-driven oncogenesis in a mouse
model of neuroblastoma and that basal inactivation
of the pathway is achieved in progressing tumors.
• Chemotoxic agents induce p53-dependent
apoptosis in such tumors. It is consistent with
clinical observations that therapy-associated
mutations in p53 are a likely contributor to the
biology of tumors at relapse and secondarily
mediate resistance to therapy.
Back
Back
Chesler L ,et al. Neoplasia 2008, 10, 1268-74
28. Treatment-induced senescence-like phenotype is
dependent on TP53 status
· In the TP53 wild-type tumor
Ki67 immunostainings were
not statistically different
before and after
treatment .
· SA-b-gal staining was
negative before treatment in
all tumors. After treatment,
5-10% tumor cells in TP53wt
showed SA-b-gal
cytoplasmic staining, as
soon as Day 1 (Figs. d–2).
· p21 immunostained cells
increased starting at Day 3
with a mean number of
stained cells over 50%
(Figs. g–i).
29. Treatment-induced mitotic catastrophe and
apoptosis is dependent on TP53 status
· The TP53 mutant tumors
remained negative for SA-b-
gal at all time points after
treatment (Figs. d–f).
· No significant change for
p21 immunostaining was
observed in the TP53 mutant
tumors (Figs. g–i).
· The number of abnormal
mitoses on semi-thin sections
significantly increased
between Day 3 and Day 5
(Figs. p–r).
31. Treatment-induced mitotic catastrophe and
apoptosis is dependent on TP53 status
· No significant change in
Bax mRNA was found in
TP53mut1 and TP53mut2
(Figs. e and h).
· Similarly PUMA showed
a strong mRNA
overexpression at D3and
D5 in TP53wt, but no
change in mutant tumors
(Figs. c, f and i)
32. Conclusion
• Treatment-induced senescence-like phenotype is
dependent on TP53 status.
• Treatment-induced mitotic catastrophe and apoptosis
is dependent on TP53 status
• The lack of response in TP53 wild-type tumors may
be due to the induction of cell cycle arrest, allowing
tumor cells to reinitiate proliferation at the end of
chemotherapy
Varna M, et al. Int J Cancer 2009, 124, 991-7
34. P53- and p21-deficient cells undergo apoptosis
after treatment with DNA-damaging agents
Cells with wild type
p53 were quite
sensitive to 5-FU, and a
large proportion
underwent apoptosis.
Cells with p21
deletions were as
sensitive to 5-FU as
p53 wild-type cells.
Bunz F, el at. J Clin Invest 1999, 104,263-9
35. Cells with targeted p53 deletion are resistant
to apoptosis induced by 5-FU
· Apoptosis was not
observed in p53-deficient
cells with 5-FU treatment.
· Tight control of 5-FU
sensitivity by p53.
· p21 does not play a role in
the ability of p53 to
modulate the response to 5-
FU.
Bunz F, el at. J Clin Invest 1999, 104,263-9
36. Cell cycle distribution of drug-treated cells
with wild-type p53 and disrupted p53 genes
· Adriamycin: p53-deficient cells
accumulated in a single peak with 4N
DNA content.
· 5-FU: regardless of p53 genotype,
cellsaccumulated in a single peak that
spanned the G1/S phase boundary.
· Tomudex: both p53-proficient and p53-
deficient cells exhibited an S-phase
block.
· Methotrexate: induced identical
responses in all cells, with an increase in
the S-phase fraction
Bunz F, el at. J Clin Invest 1999, 104,263-9
37. Characteristics of 5-FU–induced apoptosis
· Both adriamycin and 5-FU
caused increases in p53 protein
levels over a similar time course.
· The stabilization of p53 was
associated with increased levels
of p21
· 5-FU treatment led to the
dramatic induction of death in
cells with intact p53, a relatively
small proportion of cells
apparently survived and gave
rise to colonies upon replating.
38. Growth of xenograft tumors
Tumors with intact p53 genes
regressed during the
treatment, whereas the
tumors with deleted p53
genes continued to grow.
Bunz F, el at. J Clin Invest 1999, 104,263-9
39. Conclusion
• p53 had profound effects on drug responses, and
these effects varied dramatically depending on the
drug.
• The p53-deficient cells were sensitized to the
effects of DNA-damaging agents as a result of the
failure to induce expression of the cyclin-dependent
kinase inhibitor p21.
• p53 disruption rendered cells strikingly resistant to
the effects of the 5-FU.
Bunz F, el at. J Clin Invest 1999, 104,263-9
40. PFTA potentiates the antitumor effect of
cyclophosphamide
PFTa greatly potentiated the antitumor effect of cyclophosphamide, due to
the effect of the p53 inhibitor on stromal cells.
Burdelya LG ,et al. Cancer Res 2006, 66, 9356-61
42. · The levels of GSE56
expression were similar
between virus-producing and
nonproducing populations
(B)
· No EYFP expression
detected in the endothelium
of tumors formed by the cells
transduced with retroviral
vector lacking the packaging
signal as judged by
immunofluorescent staining
of tumor sections by
antibodies against mouse
endothelium marker CD31 (C,
bottom).
· Both cells producing and
not producing GSE56 virus
were equally sensitive to
treatment withseveral
chemotherapeutic drugs in
43. Dependence of tumor chemosensitivity and
radiosensitivity on the p53 status of stroma
· No differences in the growth
rate of tumors were formed
(A).
· Tumors formed by the cells
that released the p53-inhibit-
ing GSE56 virus showed a
much stronger response to
cyclophosphamide
treatment (B).
· For radiation, GSE56 virus-
producing tumors showed
significant size reduction,
whereas Δ ψ-GSE56 tumors
responded only with a slight
decline in growth rate (C.D)
· PFTa strongly sensitized
Δ ψ-GSE56 tumors to
radiation.
44. Conclusion
• Tumors with p53-deficient stroma were significantly
more sensitive to experimental chemotherapy and
radiotherapy.
• Potentiation of the anticancer effect of chemotherapy
and radiotherapy by p53 suppression in the tumor
stroma is likely to be due to the increased sensitivity
of p53-deficient endothelium to genotoxic stress as
shown both in cell culture and in experimental
tumors.
Burdelya LG ,et al. Cancer Res 2006, 66, 9356-61
45. p53 and chemotherapy
1.Introduction
1.Introduction
2. Relationship between p53 and chemotherapy
2. Relationship between p53 and chemotherapy
3. Summary
3. Summary
46. Summary
• p53 pathway plays a significant role in
chemotherapy.
• p53 Induce cell death and cell circle arrest. Their
balance contribute to the response of chemotherapy.
• Effects of p53 in chemotherapy varied dramatically
depending on the drug.
• Tumors with p53-deficient stroma were significantly
more sensitive to chemotherapy.