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1、Chapter 5 2012 Marchal et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http:/creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work
2、 is properly cited. Apoptosis as a Therapeutic Target in Cancer and Cancer Stem Cells: Novel Strategies and Futures Perspectives Mara A. Garca, Esther Carrasco, Alberto Ramrez, Gema Jimnez, Elena Lpez-Ruiz, Macarena Pern, Manuel Picn, Joaqun Campos, Houria Boulaiz and Juan Antonio Marchal Additional
3、 information is available at the end of the chapter http:/dx.doi.org/10.5772/48267 1. Introduction Apoptosis is an essential part of the normal development. The homeostatic balance between cell proliferation and cell death rate is critical for maintaining normal physiological processes. Aberrant reg
4、ulation of apoptotic cell death mechanisms is one of the hallmarks of cancer development and progression, and many cancer cells exhibit significant resistance to apoptosis signalling 1. Triggering of apoptosis can be achieved via the activation of two distinct molecular pathways, the extrinsic or de
5、ath receptor pathway or via the intrinsic or mitochondrial apoptotic cascades. Both pathways lead to the hierarchical activation of a family of cysteine proteases called caspases 2, that cleave a series of cellular substrates which induce changes including chromatin condensation, internucleosomal DN
6、A fragmentation, membrane blebbing and cell shrinkage 3. Extrinsic pathway is activated from outside the cell by proapoptotic ligands that interact with specialized cell surface death receptors, including CD95 and TNF- related apoptosis- inducing ligand (TRAIL) receptors 4. After binding to receptor
7、s apoptosis is triggered by the intracellular formation of a death- inducing signalling complex (DISC) that consists of FAS- associated death domain (FADD) and procaspase- 8 and 10 5,6. As a result, this protein complex activates procaspase- 8 and 10 inside itself, hence triggering procaspase- 3 to
8、execute the apoptosis process 7. The mitochondria (intrinsic) pathway is activated from inside the cell by severe cell stress, such as DNA or cytoskeletal damage, inducing mitochondrial outer membrane permeabilization and transcription or post- translational activation of BH3- only proapoptotic B- c
9、ell leukemia/lymphoma 2 (Bcl- 2) family proteins 4. This permeabilization allows the release of apoptogenic proteins, including cytochrome c and second mitochondria- derived Apoptosis and Medicine 112 activator of caspase (Smac; also known as DIABLO), from the mitochondrial intermembrane space into
10、the cytosol 8. Cytochrome c assembles with apoptotic protease- activating factor-1 (Apaf- 1) to activate caspase 9. This caspase, in turn, activates the effector caspases 3, 6, and 7, which carry out apoptosis 4. Smac promotes caspase activation and apoptosis by neutralization of several IAP protein
11、s, including XIAP, c- IAP1 and c- IAP2 9,10 Chemotherapeutic agents act by inhibiting tumour cell proliferation and survival and most of them can kill tumour cells by activating common apoptotic pathways 11. Therefore, apoptosis plays an important role in the treatment of cancer as it is a popular t
12、arget of many treatment strategies. 5- fluorouracil (5- FU), an antimetabolite analogue of uracil employed primarily in the treatment of a variety of solid malignant tumours, leads to a wide range of biological effects which can act as triggers for apoptotic cell death 12,13. However, resistance to
13、the drug remains a major clinical problem. Given that many of the apoptotic regulators altered in multidrug resistant tumours have been identified, one new approach to therapy is to restore apoptotic potential through genetic or pharmacological methods 14. Moreover, since defects in the mediators of
14、 apoptosis may account for chemo- resistance, the identification of new targets involved in drug- induced apoptosis is of main clinical interest. Recently, we have identified the ds- RNA- dependent protein kinase (PKR) as a key molecular target of 5- FU involved in apoptosis induction, in a p53 - in
15、dependent manner. These results suggest the clinical importance that the PKR status could play in response to chemotherapy based on 5- FU. Moreover, the effectiveness of 5- FU cytotoxic activity induced by IFN, especially in cancer cells expressing a mutated form or lacking p53, but with a functiona
16、l PKR, might have relevant clinical application in patients 15 . The increased knowledge of some of the molecular components of the apoptosis signalling pathways has paved the way for the generation of more specific agents that target one crucial signalling component. This has allowed a change in anticancer therapy trends, from classic cytotoxic strategies to the development of new non- harmful therapies which target the apoptosis response selectively only in tumour cells. Moreover, these strate
