Apoptosis and Targeted Cancer Therpeutics Flashcards
What cancer was bcl-2 antisense therapy tried in
Metastatic melanoma
What cancer was siRNA for bcl2 used in
breast tumours –> caused robust repression in mice with xenograft
Showed apoptosis and autophagic death in cells in combination with doxorubicin
What is doxorubicin
A drug that induces functionally active CD95
What is usually overexpressed in c-myc tumours
Bcl-2 –> enables c-myc tumours to evade oncogene induced sensecence!
WHat mouse model is used eto show c-myc and bcl-2 coverexpressoin
Burkitt’s lymphoma in mice
Howvever c-myc overexpression without bcl-2 just causes masive apoptssi and tumour regression
Name the 3 BH3 mimetics
Navitoclax
Ventoclax
What are the differences between Naviotclax and ventoclax
Navitoclax inhibits BCL-XL and bcl-2
Ventoclax only inhibits BCL-2
Which anto-apoptotic protein can most BH3 mimetics not target
MCL-1 –> howver a specified MCL-1 antagonist has been developed
Where have bim peptides been shown to be effacious
in mouse models of AML
What helix blocks the BH3 groove in Bax
alpha 9 –> confirmational shape change allows its exposure before it can oligomerise and nsert into the membrane
Where is the additional BH3 binding site on Bax
between alpha helices 1 and 6
What molecules aim to bind to the BH3 additional binding site
Bax Activating Molecules (BAM) –> bind to the rear BH3 binding pocket and can killl cells
Why is TRAIL overexpressed many cancer cells
As TRAIL can enhance PI3K Signalling and enhance migration and invasion
What occurs when FADD Is releaed from the TRAIL complex
forms Complex 2 –> recruits TRADD which leads to the potent aftivation of NF-kB
Also recruity TRAF2 which activates the MAPkK pathway
What decoy trail receptor is upregulated in AML
Trail 3 esp. in CSCs
Agonistic Ab binding targeted to Trail 2 is the most successful!!
What is the function of Trail 4
It is a decoy TRAIL recepor
It has an intracellular domain that can also interfere with TRAIL 2 to impair caspase activation
Can also potentiate AKt activity
Nae two Trail antibodeies
Maptumumab
Lexatumumab
What happens in necroptosis
Instead of FADD recruiting caspase 8 it insteads recruits RIP-1, which then recruitys RIP-3 which phosphorylates MKLK which desitubas the m embrane integrity and causes necroptosis.
What are the 4 peptides smac needs
alanine, proline, valine, isoleucine1
Where have smac agonists seen the most success
Glioblastomas !! In combination with TRAIL caused the complete eradication of up to 50% of glioblastomas in mice
Name a monovalent smac-mimetic
LCL-161 –> also induces an inflammatory response leading to phagocytosis of cancer cells
What happens to embryonic mice lacking Bax or Back
fail t have complete embryonic development
These mice are resistant to a large array of apoptotic stimuli
WHAT IS OCCURRING IN MICE THAT OR BOTH BAK OR BAX NULL BUT MANAGE TO SURVIVE FOR A FEW MOTNHS
Indicates a third multidomain pro-apoptotic protein termed Bok potentially exists!
What are the 2 different models for how the BH3 only proteins work
1) Direct activation
2) Indirect activation
What defines the IAP Family
Have BIR Repeats
Baculoviral IAP Repeats
How do IAPs act to prevent apoptosis
they bind caspases and can label them for degradation by ubiquination or neddylation via the RING domain
XIAP also directly inhibits the enzymatic activity of caspases
IAPS can also prevent the assembly of caspase 8 or 10 platforms!
Do IAPS also regulate the RIP family?
YES
as can also catalyse the ubqitination of RIP1
How do IAPS increase NFkB signalling
Promotes the degradation of the IKB complex that sequesters NF-kB in the cytoplasm
How can ew target IAPS in cancer
1) Antisense olignougleotides to XIAP
2) Synthetic IAP Antagonists e.g smac mimetics
How does smac inhibit IAPs
binds and inhibits BIR2 and BIR3
