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Blood, 1 November 2007, Vol. 110, No. 9, pp. 3281-3290. Prepublished online as a Blood First Edition Paper on June 25, 2007; DOI 10.1182/blood-2007-01-065888. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-01-065888v1 110/9/3281    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 Kuhn, D. J. Articles by Orlowski, R. Z. Search for Related Content PubMed PubMed Citation Articles by Kuhn, D. J. Articles by Orlowski, R. Z. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma Deborah J. Kuhn1, Qing Chen1, Peter M. Voorhees1,2, John S. Strader2, Kevin D. Shenk3, Congcong M. Sun3, Susan D. Demo3, Mark K. Bennett3, Fijs W. B. van Leeuwen4, Asher A. Chanan-Khan5, and Robert Z. Orlowski1,2,6 1 Lineberger Comprehensive Cancer Center and 2 Department of Medicine, Division of Hematology/Oncology, University of North Carolina, Chapel Hill; 3 Proteolix, South San Francisco, CA; 4 Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands; 5 Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY; and 6 Department of Pharmacology, University of North Carolina, Chapel Hill The proteasome has emerged as an important target for cancer therapy with the approval of bortezomib, a first-in-class, reversible proteasome inhibitor, for relapsed/refractory multiple myeloma (MM). However, many patients have disease that does not respond to bortezomib, whereas others develop resistance, suggesting the need for other inhibitors with enhanced activity. We therefore evaluated a novel, irreversible, epoxomicin-related proteasome inhibitor, carfilzomib. In models of MM, this agent potently bound and specifically inhibited the chymotrypsin-like proteasome and immunoproteasome activities, resulting in accumulation of ubiquitinated substrates. Carfilzomib induced a dose- and time-dependent inhibition of proliferation, ultimately leading to apoptosis. Programmed cell death was associated with activation of c-Jun-N-terminal kinase, mitochondrial membrane depolarization, release of cytochrome c, and activation of both intrinsic and extrinsic caspase pathways. This agent also inhibited proliferation and activated apoptosis in patient-derived MM cells and neoplastic cells from patients with other hematologic malignancies. Importantly, carfilzomib showed increased efficacy compared with bortezomib and was active against bortezomib-resistant MM cell lines and samples from patients with clinical bortezomib resistance. Carfilzomib also overcame resistance to other conventional agents and acted synergistically with dexamethasone to enhance cell death. Taken together, these data provide a rationale for the clinical evaluation of carfilzomib in MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Paoluzzi, M. Gonen, G. Bhagat, R. R. Furman, J. R. Gardner, L. Scotto, V. D. Gueorguiev, M. L. Heaney, K. Manova, and O. A. O'Connor The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies Blood, October 1, 2008; 112(7): 2906 - 2916. [Abstract] [Full Text] [PDF] L. Paoluzzi, M. Gonen, J. R. Gardner, J. Mastrella, D. Yang, J. Holmlund, M. Sorensen, L. Leopold, K. Manova, G. Marcucci, et al. Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma Blood, June 1, 2008; 111(11): 5350 - 5358. [Abstract] [Full Text] [PDF] R. Z. Orlowski and D. J. Kuhn Proteasome Inhibitors in Cancer Therapy: Lessons from the First Decade Clin. Cancer Res., March 15, 2008; 14(6): 1649 - 1657. [Abstract] [Full Text] [PDF]

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