week 19 pt2

Question 1

1. Define apoptosis

Answer 1

programmed cell death

That plays in the role of  developmental  morphogens  and eliminate damage cells

Evasion of apoptosis is one of hallmark of cancer

Question 2

How is the process of apoptosis

Answer 2

• Shrink
  
  • Develop bubble like blebs
  • Chromatin degrades
  • Mitochondria break up releasing cytochrome
  • Cells break in the membrane wrapped fragments
  • Phosphatidylserine is exposed on surface which promotes phagocytosi
  • Cell fragments are removed by phagocytosis

Question 3

Why is Apoptosis is used to remove cells that are a threat

Answer 3

• Cells need be eliminated sometimes
  
  • Infected cells are killed by cytotoxic T cells
  • Removal of immune infections
  • Cells that have dna dmage

Question 4

How can apoptosis occurs

Answer 4

• Can occur two ways
  
  • Intrinsic pathway: internal signal such DNA damager and oxidative damage

Or extinctic e pathway, extrinsic signal such as death factors

Question 5

Why does caspases play a vital role in apoptosis

Answer 5

Have proteases that act like molecular scissors to cleave intracellular protein

Vital in both pathways

Caspases activate procaspases that lead to apoptic signals.

Question 6

pathways of extristic

Answer 6

FAS-LIG
FAS-R
FADD
DISC
CASP
CASP3
NUCLESE
CELL. DEATH

Question 7

Intrinsic pathway

Answer 7

DNA DAMAGE
ATM
P53
BOL-BAD
BOX-BAK
CYTOCHROME
APAF 1
CASPASE 9

Question 8

What causes cancer through apoptosis

Answer 8

• Bcl-2 protein need to be balancez
  
  • Bcl-2 is an oncogene overexpression in neuroblastoma, giloma
  • Bax isd muatate din colorrectyal cancer
  • Death signals and death receptors expression can be reduced
  • So cannot be exposed to death domain

Question 9

How does caspase promote cancer

Answer 9

• Caspases are downregulated
  
  • Caspase 9 in colorectal cancer
  • Caspase in 8 and 10 choriocarcinoma

Resistance to chemotherapy

Question 10

How does P53 effect apoptosis

Answer 10

• P53 induce apotosais in response to DNA ddmaage and cellular stress
  
  • Does this. By trnasciption dpoendent and indpendend.
  • P53 induce death receptor and pro-apopotic members of the Bcl-2 family.

Question 11

How does P53 mess up to cause cancer

Answer 11

• P53 upsets the balance of Bcl-2 and Bax proteins that regulate the release of cytochrome c

Binds with Bax to activate

It represses Bcl-2

Also activates death ligand Fas

Question 12

What are the treatment to target intrinsic pathway in apoptosis

Answer 12

BH3 mimetics – small molecules that act like BH3-only proteins to inhibit Bcl-2 – some in phase 2 clinical trials e.g. venetoclax (FDA approved).

Resistance can develop due to Bcl-2 or P53 mutations.

IAP inhibitors – eg small molecules that mimic the endogenous inhibitor SMAC

Question 13

What are the treatment to target extrinsic pathway in apoptosis

Answer 13

TRAIL (TNF- related apoptosis inducing ligand the ligand for DR4 and DR5 is normally expressed on immune cells.

Agonists (agents that increase activity) targeting this pathway are currently in Phase I and II clinical trials.

Question 14

How to prevent resistance

Answer 14

• cFLIP is a common mediator of resistance to these drugs
  
  • Common chemotherapies can down regulate FLIP

Most trials now using combination approaches

Question 15

How can inhibition of extristic pathway be inhibnited

Answer 15

by the protein c-FLIP

C-Flip binds to FADD and TRADD via a DED

Inhibits caspase 8 recruitment and activation.

Question 16

Treatment stargies to target apotosis in terms of P53.

Answer 16

Gene therapy approaches using viral vectors:

Replication deficient adenoviral vectors carrying wildtype P53 (eg Advexin)

Replication competent oncolytic vectors that only bind to P53 mutant cells (Onyx)

Small molecules that can inhibit MDM2 which is a P53 inhibitor (eg Nutlin)