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- Title
TRAIL/Apo-2L death signaling pathway and molecular targeting agents: implications for chemoresistance.
- Authors
Rosell, Rafael; Cortés-Funes, Hernán; Monzó, Mariano; Felip, Enriqueta; Barnadas, Agustí; Tarón, Miquel
- Abstract
TRAIL/Apo-2L (tumor necrosis factor-related apoptosis-inducing ligand or Apo-2 ligand) was discovered by its sequence homology to tumor necrosis factor (TNF) and CD95 ligand (Fas ligand). Recombinant soluble human TRAIL/Apo-2L is a candidate for clinical research in cancer therapy because it induces apoptosis in a broad spectrum of human cancer cell lines but not in many normal cells. It is now well-known that either ligands of death receptors or chemotherapeutic drugs can induce apoptosis in tumor cells through a common apoptotic machinery. Central to this process is a family of intracellular proteases, known as caspases. During apoptosis, they can act either as initiators in response to apoptotic signals or as effectors that finally cleave a number of vital proteins and lead to the demise of the cell. The activation of caspases is controlled via multiple signaling pathways that are described in this review. There are multiple kinases involved in survival signaling that may be targeted by novel agents. There are several compounds targeting the protein kinase Akt/PKB that may inhibit apoptosis at several levels of the caspase cascade, which are also described in this review. Akt is the major kinase which phosphorylates the proapoptotic Bcl-2 member Bad and thereby converts Bad into an anti-apoptotic form that does not induce cytochrome c release. Chemotherapeutic drugs trigger the death pathway through the release of cytochrome c from damaged mitochondria. Besides TRAIL/Apo-2L, several novel agents are described that can lead to extend the therapeutic threshold. Hopefully, clinical trials will be begun very soon to elucidate the possibility of enhancing the therapeutic effect in terms of response and, especially, survival. It is thus essential for clinical investigators to understand the distinct pathways of apoptosis and caspase activation when deciding to participate in these trials.
- Publication
Clinical & Translational Oncology, 2001, Vol 3, Issue 6, p284
- ISSN
1699-048X
- Publication type
Article
- DOI
10.1007/BF02718420