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, William J Murphy

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204 Scopus citations

Abstract

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 KB (NF-κB) 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.

Original languageEnglish (US)
Pages (from-to)303-310
Number of pages8
JournalBlood
Volume102
Issue number1
DOIs
StatePublished - Jul 1 2003
Externally publishedYes

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ASJC Scopus subject areas

  • Hematology

Cite this

Sayers, T. J., Brooks, A. D., Koh, C. Y., Ma, W., Seki, N., Raziuddin, A., Blazar, B. R., Zhang, X., Elliott, P. J., & Murphy, W. J. (2003). The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. Blood, 102(1), 303-310. https://doi.org/10.1182/blood-2002-09-2975