Apoptosis activation as a therapeutic strategy for cancer
Cell survival is maintained by a balance between pro-apoptotic and anti-apoptotic stimuli. Dysregulation of apoptosis can disrupt the equilibrium between cell growth and cell death and is an important step in the development of cancer.3,5,15,27 It is this understanding that has led to the investigation of therapeutic activation of apoptosis in cancer cells as a potential anticancer strategy.11-14
Current conventional therapies such as radio- and chemotherapy indirectly promote apoptosis, although this is an important endpoint of the therapeutic effect.27-35 These regimens induce apoptosis by causing DNA damage. In doing so, they stimulate apoptosis through the intrinsic pathway (Figure 1.4).
Figure 1.4. Chemotherapy/radiotherapy-induced and p53-mediated activation of apoptosis via the intrinsic signaling pathway.Click here to view a PDF of this image.
Adapted from Ashkenazi 2002. Reproduced with permission from Nature Reviews Cancer.
The tumor suppressor protein p53 is one of many proteins that contributes to the activation of the intrinsic signaling pathway.36,37 Inactivation of this protein or elements of its attendant pathway (upstream activators and/or downstream effectors), due to mutation, is seen in as many as half of all human cancers.38 Because of the important role of p53 in the intrinsic apoptosis pathway, such a mutation can render tumor cells resistant to conventional radio- and chemotherapy.27,33,39,40
Promoting the alternative 'extrinsic' apoptosis pathway (Figure 1.5), which operates independently of p53,41 or augmenting downstream elements of the intrinsic apoptosis pathway3 may have the potential to induce apoptosis both in cancer cells that are responsive and in those that have become resistant to conventional therapies.38,42-47
Figure 1.5. Potential therapeutic targets for apoptosis promotion.Click here to view a PDF of this image.
Adapted from Ashkenazi 2002. Reproduced with permission from Nature Reviews Cancer.