Therapeutic applications of TRAIL receptor agonists in cancer and beyond.
TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings - ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future.
Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, SP, Brazil; Instituto de Investigação em Imunologia, Instituto Nacional de Ciência e Tecnologia, Brazil. Electronic address: gpam@usp.br.
Gustavo P
GP
Amarante-Mendes
Department of Urology, Masonic Cancer Center, Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Minneapolis VA Health Care System, Minneapolis, MN 55417, USA. Electronic address: tgriffit@umn.edu.
Thomas S
TS
Griffith
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000276:immunology / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand
Apoptosis; Cancer; Cell death; Immune therapy; TRAIL