Intracellular Acidosis Promotes Mitochondrial Apoptosis Pathway ...
Novel agents targeting the apoptosis pathway
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Novel agents targeting the apoptosis pathway Aaron D. Schimmer MD, PhD, FRCPC Princess Margaret Hospital Toronto, Canada
description
Novel agents targeting the apoptosis pathway. Aaron D. Schimmer MD, PhD, FRCPC Princess Margaret Hospital Toronto, Canada. Cancer is an Elephant. Cancer is a defect In apoptosis. Therapy. Biology. Apoptosis. Survival. Survival. Survival. Survival. Death. Death. Death. Death. - PowerPoint PPT Presentation
Transcript of Novel agents targeting the apoptosis pathway
Novel agents targeting the apoptosis pathway
Aaron D. Schimmer MD, PhD, FRCPCPrincess Margaret HospitalToronto, Canada
Cancer is an Elephant
Cancer is a defectIn apoptosis
Therapy Biology
Apoptosis
Ask1Ask1
FADD ApafApaf --11Casp -9Casp -9
Casp -3Casp -3
Casp -7Casp -7Casp -6Casp -6
BADBADCasp -8
AktAkt
Cyt-c
p53
Death SubstratesDeath SubstratesICAD/DFF; PARP; ICAD/DFF; PARP; GelsolvinGelsolvin , etc., etc.
IAPsIAPs
BAXBcl -2
Bcl -XLBfl-1
PUMA NOXA
NF-kB
IkB
IKK
PI3K
FasFas --L geneL gene
FKHDFKHD
Nur77(TR3)
FasDR5
NF-kB
FlipPTEN
DeathDeathReceptorsReceptors
SurvivalSurvivalReceptorsReceptors
Reed JC, NDDR, 2002
Ask1Ask1
FADD ApafApaf --11Casp -9Casp -9
Casp -3Casp -3
Casp -7Casp -7Casp -6Casp -6
BADBADCasp -8
AktAkt
Cyt -c
p53
Death SubstratesDeath SubstratesICAD/DFF; PARP; ICAD/DFF; PARP; GelsolvinGelsolvin , etc., etc.
IAPsIAPs
BAXBcl -2
Bcl -XLBfl -1
PUMA NOXA
NF-B
IB
IKK
PI3K
FasFas -- L geneL gene
FKHDFKHD
Nur77(TR3)
FasDR5
NF-B
FlipPTEN
DeathDeathReceptorsReceptors
SurvivalSurvivalReceptorsReceptors
Reed JC, NDDR, 2002
MitochondriaMitochondria
CytochromeCytochrome--CC
Caspase-9Caspase-
3
Caspase-8
Fadd/ mort1
FAS/TRAIL
+Apaf-
1
Mitochondrial –Mediated (Intrinsic Pathway)
Receptor Mediated (Extrinsic Pathway)
MitochondriaMitochondria
CytochromeCytochrome--CC
Caspase-9Caspase-
3
Caspase-8
Fadd/ mort1
FAS/TRAIL
Granzyme BGranzyme B
+Apaf-
1
Mitochondrial –Mediated (Intrinsic Pathway)
Receptor Mediated (Extrinsic Pathway)
FLIP
MitochondriaMitochondria
CytochromeCytochrome--CC
Caspase-9Caspase-
3
Caspase-8
Fadd/ mort1
FAS/TRAIL
Granzyme BGranzyme B
+Apaf-
1
Mitochondrial –Mediated (Intrinsic Pathway)
Receptor Mediated (Extrinsic Pathway)
XIAP
? Casp –3/7inhibition
Ubiquitination
BIR 1BIR 1 RING BIR 2BIR 2 BIR 3BIR 3
Casp –9inhibition
XIAP structure –functionXIAP structure –function
MitochondriaMitochondria
CytochromeCytochrome--CC
Caspase-9Caspase-
3
Caspase-8
Fadd/ mort1
FAS/TRAIL
Granzyme BGranzyme B
+Apaf-
1
Mitochondrial –Mediated (Intrinsic Pathway)
Receptor Mediated (Extrinsic Pathway)
Bcl-2
MitochondriaMitochondria
CytochromeCytochrome--CC
Caspase-9Caspase-
3
Caspase-8
Fadd/ mort1
FAS/TRAIL
Granzyme BGranzyme B
+Apaf-
1
Mitochondrial –Mediated (Intrinsic Pathway)
Receptor Mediated (Extrinsic Pathway)
XIAP
FLIP
Bcl-2
•
Bcl-2: apoptosis and cell Bcl-2: apoptosis and cell cyclecycle
MitochondriaMitochondria
Cyto-cCyto-c
Bcl-2Bcl-2
Bax
M
S
G1 G2
Strategies to inhibit Bcl-2
Antisense Oligonucleotides
ChemicalBcl-2 Inhibitors
Bcl-2 ProteinBcl-2 Protein
Bcl-2 ProteinBcl-2 Protein(with BH3 Peptide)(with BH3 Peptide)
