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Apoptosis and response to
chemotherapy
Content
• Apoptosis – what is it?
• Apoptosis vs necrosis
• Radiation vs chemotherapy
• Apoptosis vs mitosis
• Tumour hija...
Apoptosis
 “Apoptosis is a cell suicide mechanism
that enables metazoans to control cell
number in tissues and to elimina...
Inhibition of apoptosis underlies many
carcinogenic processes
• Growth in the absence of normal growth
signals
• Growth in...
FADD
TNFR1
NF
TRADD
FADDTRAF-2
RIP
TNFα
C-FLIP
Caspases 3, 6, 7
SURVIVAL
SIGNALS
Caspase 9
FAS
FAS-L
NUCLEUS
tBID/BAX
Ca...
3 main apoptotic pathways
•Extrinsic
•Intrinsic
•Interaction between activated CTL
receptors and MHC-class 1 molecules
SENSITIZERS
PRO-APOPTOTIC
p53, Smac/Diablo, Omi/HtrA2,
Bik, Bim, Bad, Noxa, Puma, Noxa, Bmf,
Bid, Bax, Bak, JNK, APAF-1,
c...
FADD
TNFR1
NF
TRADD
FADDTRAF-2
RIP
TNFα
C-FLIP
Caspases 3, 6, 7
SURVIVAL
SIGNALS
Caspase 9
FAS
FAS-L
NUCLEUS
tBID/BAX
Ca...
BH3 only “Trigger” proteins
Bik, Bim, Bid, Bmf, Puma, Noxa, Bad
Anti-apoptotic “Arbitrator” proteins
Bcl-2, BclXL, Bcl-w, ...
Activation of initiator
caspases in apoptosome or DISC
Activation of executioner
caspases by active
initiator caspases
IAP...
Necrosis vs Apoptosis
Taken from Cytometry 1997
Cancer therapies can induce
apoptosis
• Irradiation
DNA strand breaks
Free radical formation
Ceramide (independent of DNA ...
Successful chemotherapy?
Drug
cure
+
Stem cells
A tumour will not evolve if its stem cells are
prevented from continued cell proliferation
Cell death after radiation
• Apoptosis
• Mitotic catastrophe
• Terminal growth arrest (senescence)
Tumours can hijack
apoptosis
regulatory mechanisms in normal cells
to guard against inadvertent apoptosis
mechanisms hijac...
• Downregulation of Fas
•Prevalance of Fas-L expressing tumour cells
Fas TIL killed by Fas-L expressing tumour cells
? Downregulation of MHC class 1 molecules on tumour cells
Successful chemotherapy
Drug
Stem cell
regrowth
Oncogenes
TSG
Controlled destruction of certain cells
Pro
apoptotic
Anti-a...
MMC Response Pathways
Mitomycin-C +
DNA repair
No drug-target interaction
No
effect
DNA
mutation
Apoptosis
p53
Bcl2
Cellul...
Immunostaining as an adjunct in
pathology
• Antibodies raised against biomarkers
• Biomarkers can be localised in tissue
s...
Mitochondrial role
Bcl-2
p53
Bax Bak
Pore formation
Bcl-2 associated with cisplatin resistance
Bcl-2 :Bax ratios predictive
BH3 mimetics
• Some function as death agonists directly
mimicking the activity of tBid
• Others have been synthesized on t...
TRAIL ? Therapeutic agent
• TRAIL is tumour necrosis factor–related
apoptosis-inducing ligand
• TRAIL induces apoptosis in...
Carcinogen
Ionising radiation
Mutagen
DNA damage
p53 activated
DNA repair BAX
apoptosisNormal cell
success fail
 Bcl-2
J...
DNA repair as a target
DNA repair
Carcinogen
Ionising radiation
Mutagen
DNA damage
p53 activated
BAX
apoptosisTumour cell...
Current Strategies
Drug Target
CCDO FLIP
PRIMA-1 Mutant p53
Embelin IAPs
Genasense Bcl-2
Gossypol Bcl-2
HGS-ERT1 TRAIL
BH3...
TNF α
PROLIFERATION/
SURVIVAL
INFLAMMATION APOPTOSIS
NF-кB
ONCOGENIC RAS Bcl-2
p53JNK
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Apoptosis and the response to chemotherapy

  1. 1. Apoptosis and response to chemotherapy
  2. 2. Content • Apoptosis – what is it? • Apoptosis vs necrosis • Radiation vs chemotherapy • Apoptosis vs mitosis • Tumour hijacking apoptosis • Therapeutic strategies
  3. 3. Apoptosis  “Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal’s survival” Ashkenazi, Science 1998
  4. 4. Inhibition of apoptosis underlies many carcinogenic processes • Growth in the absence of normal growth signals • Growth in the presence of growth inhibitory factors • Metastases • Chemoresistance • Promotion of angiogenesis
  5. 5. FADD TNFR1 NF TRADD FADDTRAF-2 RIP TNFα C-FLIP Caspases 3, 6, 7 SURVIVAL SIGNALS Caspase 9 FAS FAS-L NUCLEUS tBID/BAX Caspase 8 IAPS ENDO G & AIF UV CYTOKINE DEPRIVATION STEROID Bcl-2 BH3 only ROS DISC ATR/ATM/DNA PK STRESS / DNA DAMAGE CHEMOTHERAPY p53 SMAC/DIABLO JNK jBID CTL/NK cell Granzymes APOPTOSOME
  6. 6. 3 main apoptotic pathways •Extrinsic •Intrinsic •Interaction between activated CTL receptors and MHC-class 1 molecules
  7. 7. SENSITIZERS PRO-APOPTOTIC p53, Smac/Diablo, Omi/HtrA2, Bik, Bim, Bad, Noxa, Puma, Noxa, Bmf, Bid, Bax, Bak, JNK, APAF-1, cytochrome c ANTI-APOPTOTIC Bcl-2, BclXL, Bcl-w, A1, Mcl-1, IAPs, Heat shock proteins STIMULATORS Fas, TNF, TGF, IFN, ROS, CTL, viruses, steroids, staurosporin, hypoxia, telomere erosion, X-rays, UV, DNA damage, hormones, Ca2+ flux PROCESSORS DFF40, Endo G, DNase II, AIF, Proteases
  8. 8. FADD TNFR1 NF TRADD FADDTRAF-2 RIP TNFα C-FLIP Caspases 3, 6, 7 SURVIVAL SIGNALS Caspase 9 FAS FAS-L NUCLEUS tBID/BAX Caspase 8 IAPS ENDO G & AIF UV CYTOKINE DEPRIVATION STEROID Bcl-2 BH3 only ROS DISC ATR/ATM/DNA PK STRESS / DNA DAMAGE p53 SMAC/DIABLO JNK jBID CTL/NK cell Granzymes APOPTOSOME
  9. 9. BH3 only “Trigger” proteins Bik, Bim, Bid, Bmf, Puma, Noxa, Bad Anti-apoptotic “Arbitrator” proteins Bcl-2, BclXL, Bcl-w, A1, Mcl-1 “Killer” proteins Bax and Bak Bcl-2 gene family
  10. 10. Activation of initiator caspases in apoptosome or DISC Activation of executioner caspases by active initiator caspases IAPS Smac/Diablo Demolition of the cell P P P P L S L L L L L L L S S S S S S S Critical role of caspases
  11. 11. Necrosis vs Apoptosis
  12. 12. Taken from Cytometry 1997
  13. 13. Cancer therapies can induce apoptosis • Irradiation DNA strand breaks Free radical formation Ceramide (independent of DNA damage) • Chemotherapy DNA crosslinks toxic effects death receptor upregulation
  14. 14. Successful chemotherapy? Drug cure +
  15. 15. Stem cells A tumour will not evolve if its stem cells are prevented from continued cell proliferation
  16. 16. Cell death after radiation • Apoptosis • Mitotic catastrophe • Terminal growth arrest (senescence)
  17. 17. Tumours can hijack apoptosis regulatory mechanisms in normal cells to guard against inadvertent apoptosis mechanisms hijacked by tumour cells
  18. 18. • Downregulation of Fas •Prevalance of Fas-L expressing tumour cells Fas TIL killed by Fas-L expressing tumour cells
  19. 19. ? Downregulation of MHC class 1 molecules on tumour cells
  20. 20. Successful chemotherapy Drug Stem cell regrowth Oncogenes TSG Controlled destruction of certain cells Pro apoptotic Anti-apoptotic
  21. 21. MMC Response Pathways Mitomycin-C + DNA repair No drug-target interaction No effect DNA mutation Apoptosis p53 Bcl2 Cellular response Fas Environmental factors
  22. 22. Immunostaining as an adjunct in pathology • Antibodies raised against biomarkers • Biomarkers can be localised in tissue sections
  23. 23. Mitochondrial role Bcl-2 p53 Bax Bak Pore formation Bcl-2 associated with cisplatin resistance Bcl-2 :Bax ratios predictive
  24. 24. BH3 mimetics • Some function as death agonists directly mimicking the activity of tBid • Others have been synthesized on the premise that they will inhibit the anti- apoptotic function of Bcl-2 and Bcl-xL.
  25. 25. TRAIL ? Therapeutic agent • TRAIL is tumour necrosis factor–related apoptosis-inducing ligand • TRAIL induces apoptosis independently of p53 • TRAIL demonstrates preferential apoptosis induction in tumour cells while sparing most normal cells
  26. 26. Carcinogen Ionising radiation Mutagen DNA damage p53 activated DNA repair BAX apoptosisNormal cell success fail  Bcl-2 Jia Li, Liau 2007
  27. 27. DNA repair as a target DNA repair Carcinogen Ionising radiation Mutagen DNA damage p53 activated BAX apoptosisTumour cell  Bcl-2 Jia Li, Liau 2007 ?????
  28. 28. Current Strategies Drug Target CCDO FLIP PRIMA-1 Mutant p53 Embelin IAPs Genasense Bcl-2 Gossypol Bcl-2 HGS-ERT1 TRAIL BH3 mimetics Anti-apoptotic proteins Bortezomib (VELCADE) 26S proteosome MKT-007 mitochondria IRESSA growth factor receptor
  29. 29. TNF α PROLIFERATION/ SURVIVAL INFLAMMATION APOPTOSIS NF-кB ONCOGENIC RAS Bcl-2 p53JNK
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    Jun. 30, 2016

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