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Cancer therapy strategies (Cell Death in cancer (Apoptosis (Caspases…
Cancer therapy strategies
Cell Death in cancer
Necrosis
Apoptosis
Caspases Important
Executioner (pro-domain)
Initiator
Extrinsic factor pathway of apoptosis
Extrinsic
Type 1
Type 2
Types differ by the need of intrinsic activation
Intrinsic factor pathway
Bcl-2 family as effector
Anti
Pro
Bh3 only
Cytosolic p53
Regulates apoptosis
also trancription factor
Disruption of Apoptotic mechanisms
Disruption of FAS (first apoptotic signal)
Disruption of Bcl-2 protein balance
commonly upregulated in leukemia
anti BLC drugs
Dysregulation of inhibitor of Apoptosis (IAPs)
Survivin over expression
Downregulation of XAF1
Mutation of caspases in cancer
Targeting apoptosis as therapeutic strategy
Targeted TNF-related apoptosis inducing Ligand(TRAIL)
Targeting Bcl-2 family
BH3 mimetics
Navitoclax
Venetoclax
No MCL targeted drugs currently
Multiple pathways simultaneously need to be targeted
Targeting IAPs
Regulation of IAPs controlling proteins
Smac-proteins as XIAP inhibiting molecules
Produce Caspase inhibition
Targeting Caspases in cancer
Has not been succesful
Cytotoxicity
DNA MUTATIONS in cancer
Type of mutations
Mutation in the promoter
disrupted gene regulation
Over/under expression
defect in protein localisation
mutation in the coding region
Altered protein structure
Abolish protein function completely
Driver mutations 10-15
Carcinogenic agents
Chemical
Infectious pathogenes as carcinogenes
Radiation
Endogenous carcinogenic reactions
Exogenous ROS
Endogaenous ROS
LEAD TO OXYGEN DAMAGE
Summary on effects on slides
kataegis v.s chromothipsis
carsinogenesis
Conventional therapy
Organic