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.2,7-9 It is this understanding that has led to the investigation of therapeutic activation of apoptosis in cancer cells as a potential anticancer strategy.10-13
Current conventional therapies such as radio– and chemotherapy exert their therapeutic effect by indirectly promoting apoptosis.9,14-21 These regimens induce apoptosis by causing DNA damage. In doing so, they stimulate apoptosis through the intrinsic pathway (Figure 3.1).
The tumor suppressor protein p53 is one of many proteins that contributes to the activation of the intrinsic signaling pathway.22,23 Inactivation of this protein or the p53 pathway (upstream activators and/or downstream effectors), due to mutation, is seen in as many as half of all human cancers.24 Because of the important role of p53 in the intrinsic apoptotic pathway, such a mutation can render tumor cells resistant to conventional radio- and chemotherapy.9,19,25,26 Furthermore, conventional radiotherapy and chemotherapeutics induce apoptosis only as a secondary effect of the damage they cause to vital cellular components and cannot discriminate between malignant or normal cell types.27
Promoting the alternative extrinsic apoptotic pathway (Figure 3.1), which operates independently of p53,28 or augmenting downstream elements of the intrinsic apoptotic pathway7 may have the potential to induce apoptosis both in responsive and resistant cancer cells.24,29-34
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Figure 3.1. Potential therapeutic targets for apoptotic promotion. |
