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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 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 Citation Map 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. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 July 2003, Vol. 102, No. 1, pp. 303-310 NEOPLASIA 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 From the Basic Sciences Program, SAIC-Frederick, the Laboratory of Molecular Immunoregulation, and the Laboratory of Experimental Immunology, National Cancer Institute—Center for Cancer Research, Frederick, MD; the Cancer Center and Department of Pediatrics, Division of BMT, University of Minnesota, Minneapolis; and Millennium Pharmaceuticals, Cambridge, MA. Because of 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 nuclear factor B (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. (Blood. 2003;102:303-310) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. H. Cheung, D. J. Mahoney, E. C. LaCasse, and R. G. Korneluk Down-regulation of c-FLIP Enhances Death of Cancer Cells by Smac Mimetic Compound Cancer Res., October 1, 2009; 69(19): 7729 - 7738. [Abstract] [Full Text] [PDF] A. Lundqvist, H. Yokoyama, A. Smith, M. Berg, and R. Childs Bortezomib treatment and regulatory T-cell depletion enhance the antitumor effects of adoptively infused NK cells Blood, June 11, 2009; 113(24): 6120 - 6127. 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