Regulating apoptosis
Apoptosis occurs via two main signaling pathways — (a) the intrinsic and (b) the extrinsic pathways (Figure 1.3), both of which are potential anticancer therapeutic targets.6-8 The intrinsic pathway is triggered from within the cell by developmental cues or severe cell stress, such as DNA damage. The extrinsic pathway is activated when a pro-apoptotic ligand, such as endogenous Fas ligand or APO2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL), binds to pro-apoptotic receptors, such as Fas, or DR4 and DR5. Destruction of the cell is ultimately carried out by intracellular protease enzymes called caspases that, on activation through the intrinsic and/or extrinsic pathways, destroy cellular proteins that are vital for cell survival.9,10
Figure 1.3. Overview of the two major apoptosis pathways.Click here to view a PDF of this image.
Adapted from Ashkenazi 2002. Reproduced with permission from Nature Reviews Cancer.
The activation or restoration of apoptosis is emerging as a key strategy to treat cancer and other diseases.7,8,11-14 Conventional cancer therapies (radio- and chemotherapy) have limitations in treating metastatic disease because of the existence or development of treatment-resistant tumor cells.15 Although advances continue to be made in terms of novel and combination radio- and chemotherapy regimens, clinical studies consistently show that there are many patients across the range of human malignancies who experience disease progression and recurrence with these therapies.16-26 These patients represent a significant unmet medical need.