The potential of TRAIL for cancer chemotherapy |
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Authors: | M. Nagane H.-J. S. Huang W. K. Cavenee |
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Affiliation: | (1) Department of Neurosurgery, Kyorin University School of Medicine, Mitaka, Tokyo, 181-8611, Japan;(2) Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, 92093-0660;(3) Ludwig Institute for Cancer Research, Department of Medicine, University of California at San Diego, La Jolla, CA, 92093-0660;(4) Ludwig Institute for Cancer Research, Department of Medicine, Center for Molecular Genetics, Cancer Center, University of California at San Diego, La Jolla, CA, 92093-0660 |
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Abstract: | Innate and acquired resistance to chemotherapy and radiation therapy has been a major obstacle for clinical oncology. One potential adjunct to such conventional treatments is direct induction of cell death by activation of death receptor-mediated apoptosis. TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand), a recently identified member of the growing TNF superfamily, binds to its cognate death receptors DR4 and DR5 as well as decoy receptors DcR1 and DcR2. Upon binding, rapid apoptosis is enacted in a variety of human cancer cell lines independent of p53 status, but not in normal cell lines. TRAIL treatment results in significant growth suppression of TRAIL-sensitive human cancer xenografts in mice. Furthermore, combination treatment of TRAIL with genotoxic chemotherapeutic agents synergistically suppresses growth of tumor xenografts which are otherwise resistant to treatment with TRAIL or chemotherapy alone. Unlike the other death ligands TNF- or FasL, systemic administration of soluble human TRAIL does not cause toxicity in mice and non-human primates. While further studies are needed to evaluate the possible cytotoxicity of TRAIL especially for human hepatocytes, indications are increasing that TRAIL may be a novel therapeutic agent for human cancer. |
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Keywords: | apoptosis cancer therapy death ligand death receptor DNA damage DR5 TNF superfamily TNFR superfamily TRAIL |
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