Apoptosis and its relevance in cancer therapy.
In the majority of human tumors the ability to induce programmed cell death (apoptosis) is frequently lost, suggesting that disruption of the apoptotic function contributes significantly to the transformation of a normal cell into a tumor cell. Apoptosis is regulated by two major pathways, the death receptor-induced and the stress-mediated pathway. While the former depends on the activation of death receptors such as Fas-R, the latter is induced by various stress signals. Stimulation of the death receptor pathway directly triggers the proteolytic activation of caspases via the formation of a death receptor- induced signalling complex (DISC). In contrast, caspase activation via the stress-induced pathway is mediated by the formation of a protein complex called apoptosome which forms upon release of cytochrome c regulated by members of the Bcl-2 protein family. Ultimately, both pathways disembogue into cellular changes, eventually causing the cell death. Mutation of many different genes involved in the regulation of apoptosis have been identified in human cancer, resulting in the development of novel therapeutic approaches such as activation of death receptors using recombinant ligand or inhibition of Bcl-2 expression by antisense reagents. Although based on different targets and delivery methods, all these approaches have the common goal to eliminate tumor cells by restoration of the apoptotic function.