Regulating apoptosis
Apoptosis occurs via 2 main signaling pathways — 1) the intrinsic pathway, and 2) the extrinsic pathway (Figure 1.3), both of which are potential anticancer therapeutic targets.8-10 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 death receptors, such as Fas, or death receptor 4 (DR4) and death receptor 5 (DR5). Destruction of the cell is ultimately carried out by intracellular protease enzymes called caspases that, upon activation of the intrinsic and/or extrinsic pathways, destroy cellular proteins that are vital for cell survival.11,12
|
|
Click here to view a PDF of this image.
Figure 1.3. Overview of the 2 major apoptotic pathways. |
The activation or restoration of apoptosis is emerging as a key strategy to target cancer and other diseases.9,10,13-16 Conventional cancer therapies (radio- and chemotherapy) have limitations in treating metastatic disease because of the existence or development of treatment-resistant tumor cells.17 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.18-28