ntrinsic pathway
As its name suggests, the intrinsic, or mitochondrial, pathway is initiated from within the cell (Figure 3.1).3
This pathway is often activated in response to signals resulting from DNA damage, loss of cell-survival factors, or other types of severe cell stress. Normally, pro-apoptotic proteins are released from the mitochondria to activate caspase proteases and trigger apoptosis.3

Enlarge this image
When these pro-apoptotic signals are not released, the cell cannot die.1 The intrinsic pathway hinges on the balance of activity between pro- and anti-apoptotic signals of the Bcl-2 family.14 Preclinical studies indicate that members of the Bcl-2 family regulate the permeability of the mitochondrial membrane and determine whether a pro- or anti-apoptotic signal will be released inside the cell.15
Research implies that in this cascade, the anti-apoptotic proteins (eg, Bcl-XL) antagonize Bax and Bak by binding to their BH3 domains. This antagonism is relieved by BH3-only, pro-apoptotic proteins (eg, BIM, BID, BAD, NOXA, PUMA), which alternately bind to anti-apoptotic proteins, like Bcl-XL. In normal cells, cellular stress would result in an upregulation of these BH3-only proteins in order to initiate apoptosis via the intrinsic apoptotic pathway.3
Currently, the intrinsic pathway is more widely implicated as a blockade to tumorigenesis.2
Extrinsic pathway
The extrinsic pathway begins outside the cell through activation of pro-apoptotic receptors on the cell surface. These are activated by molecules known as pro-apoptotic ligands.12
Preclinical studies show that ligand binding causes receptors to cluster and ultimately form a death-inducing signaling complex (DISC).12
Upon DISC activation, the extrinsic pathway has been seen to adopt the same effector caspase machinery as the intrinsic pathway.12

The Bcl-2 family: regulators of cell survival
Survival of cancer cells is influenced by the interactions between pro- and anti-apoptotic proteins (Table 4.1).3

Enlarge this image
In normally functioning cells, the “apoptotic trigger” is initiated when pro- and anti-apoptotic members of the Bcl-2 family are unbalanced.2 When these factors are out of balance, the apoptotic trigger no longer functions and cells are allowed to proliferate.2 One way