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Apoptosis and the response to chemotherapy
- 1. Apoptosis and response to chemotherapy
- 2. Content • Apoptosis – what is it? • Apoptosis vs necrosis • Radiation vs chemotherapy • Apoptosis vs mitosis • Tumour hijacking apoptosis • Therapeutic strategies
- 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. 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. 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. 3 main apoptotic pathways •Extrinsic •Intrinsic •Interaction between activated CTL receptors and MHC-class 1 molecules
- 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. 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. 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. 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
- 12. Taken from Cytometry 1997
- 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
- 15. Stem cells A tumour will not evolve if its stem cells are prevented from continued cell proliferation
- 16. Cell death after radiation • Apoptosis • Mitotic catastrophe • Terminal growth arrest (senescence)
- 17. Tumours can hijack apoptosis regulatory mechanisms in normal cells to guard against inadvertent apoptosis mechanisms hijacked by tumour cells
- 18. • Downregulation of Fas •Prevalance of Fas-L expressing tumour cells Fas TIL killed by Fas-L expressing tumour cells
- 19. ? Downregulation of MHC class 1 molecules on tumour cells
- 20. Successful chemotherapy Drug Stem cell regrowth Oncogenes TSG Controlled destruction of certain cells Pro apoptotic Anti-apoptotic
- 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. Immunostaining as an adjunct in pathology • Antibodies raised against biomarkers • Biomarkers can be localised in tissue sections
- 23. Mitochondrial role Bcl-2 p53 Bax Bak Pore formation Bcl-2 associated with cisplatin resistance Bcl-2 :Bax ratios predictive
- 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. 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. Carcinogen Ionising radiation Mutagen DNA damage p53 activated DNA repair BAX apoptosisNormal cell success fail Bcl-2 Jia Li, Liau 2007
- 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. 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. TNF α PROLIFERATION/ SURVIVAL INFLAMMATION APOPTOSIS NF-кB ONCOGENIC RAS Bcl-2 p53JNK