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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.
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Submitted January 3, 2007
Accepted June 18, 2007
Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against pre-clinical models of multiple myeloma
Deborah J. Kuhn, Qing Chen, Peter M. Voorhees, John S. Strader, Kevin D. Shenk, Congcong M. Sun, Susan D. Demo, Mark K. Bennett, Fijs W. B. van Leeuwen, Asher A. Chanan-Khan, and Robert Z. Orlowski*
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
Department of Medicine, Division of Hematology/Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
Proteolix, Inc., South San Francisco, CA, United States
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam, Netherlands
Dept. of Medicine, Roswell Park Cancer Institute, Buffalo, NY, United States
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
* Corresponding author; email: r_orlowski{at}med.unc.edu.
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, while others develop resistance, suggesting the need for other inhibitors with enhanced activity, and 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 JNK, 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, as well as neoplastic cells from patients with other hematologic malignancies. Importantly, carfilzomib showed increased efficacy compared to 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.
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