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Prepublished online as a Blood First Edition Paper on March 13, 2003; DOI 10.1182/blood-2002-09-2975. This Article Full Text (PDF) All Versions of this Article: 2002-09-2975v1 102/1/303    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sayers, T. J Articles by Murphy, W. J Search for Related Content PubMed PubMed Citation Articles by Sayers, T. J Articles by Murphy, W. J Social Bookmarking                   What's this? Submitted October 1, 2002 Accepted March 4, 2003 The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP Thomas J Sayers*, Alan D Brooks, Crystal Y Koh, Weihong Ma, Naoko Seki, Arati Raziuddin, Bruce R Blazar, Xia Zhang, Peter J Elliott, and William J Murphy Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, USA Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA Department of Drug Development, Millennium Pharmaceuticals, Boston, MA, USA * Corresponding author; email: sayers{at}mail.ncifcrf.gov. Due to the pivotal role the proteasome plays in apoptosis, inhibitors of this enzyme, such as PS-341, provide a great opportunity for exploring synergy between proteasome inhibition and other apoptosis-inducing agents. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) can selectively induce apoptosis in tumor cells. In overnight assays, combinations of PS-341 and TRAIL were much more effective than either agent alone in promoting apoptosis of a murine myeloid leukemia C1498 and a murine renal cancer Renca. For C1498 cells, apoptosis sensitization by PS-341 affected neither the activity of NF-B, nor the levels of most antiapoptotic proteins. However, reductions in the antiapoptotic protein c-FLIP in response to PS-341 were observed in both C1498 and Renca cells. Treatment of normal bone marrow mixed with C1498 tumor cells for 18 hours with a combination of PS-341 and TRAIL resulted in a specific depletion of the tumor cells. Upon transfer to irradiated syngeneic recipient mice mixtures treated with the PS-341 plus TRAIL combination resulted in enhanced long-term tumor-free survival of mice. These data therefore support the targeting of apoptotic pathways in tumor cells, using combinations of agents such as PS-341 and TRAIL that interact synergistically to preferentially promote tumor cell apoptosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. Sun, M. Li, T. J. Sayers, L. A. Welniak, and W. J. Murphy Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation Blood, August 15, 2008; 112(4): 1522 - 1529. [Abstract] [Full Text] [PDF] J. Begley and A. Ribas Targeted Therapies to Improve Tumor Immunotherapy Clin. Cancer Res., July 15, 2008; 14(14): 4385 - 4391. [Abstract] [Full Text] [PDF] C. Li, R. Li, J. R. Grandis, and D. E. Johnson Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells Mol. 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