The Long and Winding Road to Cancer Treatment: The Trail System
Activation of cell surface death receptors of the tumor necrosis factor (TNF) receptor superfamily by the appropriate ligands
represents an attractive therapeutic strategy to induce cell death by apoptosis in cancer cells. However, the toxic effects of TNF-alpha and
CD95/Fas ligand (FasL) in normal tissues have significantly hampered the clinical application of these ligands in cancer treatment. TNFrelated
apoptosis-inducing ligand (TRAIL/APO-2L), another member of the TNF family, has been shown to induce apoptosis selectively
in many tumor cell lines. Interestingly, TRAIL treatment also results in significant growth suppression of TRAIL-sensitive human cancer
xenografts in mice and nonhuman primates. At the same time, recombinant TRAIL and agonistic TRAIL receptor antibodies show no
significant cytotoxicity in these studies. Despite some adverse effects of certain TRAIL preparations, activation of proapoptotic TRAIL
receptors represents a promising approach in cancer therapy. Herein we review what is known about proapoptotic TRAIL signaling, the
role of intracellular survival pathways in the regulation of resistance to TRAIL and the activation of non-apoptotic signaling by TRAIL.
We also discuss the role of the TRAIL system in tumorigenesis and the results of clinical trials with recombinant TRAIL and various
TRAIL receptor agonistic antibodies, either as monotherapy or in combination with targeted or conventional chemotherapy.
Keywords: TRAIL signaling, tumorigenesis, therapeutic potential, cancer, clinical trials.
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