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Blood, 7 May 2009, Vol. 113, No. 19, pp. 4667-4676.
Prepublished online as a Blood First Edition Paper on December 2, 2008; DOI 10.1182/blood-2008-07-171637.
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Submitted July 31, 2008
Accepted November 24, 2008
Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and non-specific proteasome inhibitors
Deborah J. Kuhn, Sally A. Hunsucker, Qing Chen, Peter M. Voorhees, Marian Orlowski, and Robert Z. Orlowski*
Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
Department of Pharmacology, Mount Sinai School of Medicine, New York, NY, United States
Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: rorlowsk{at}mdanderson.org.
Proteasome inhibition is a validated strategy for therapy of multiple myeloma, but this disease remains challenging as relapses are common, and often associated with increasing chemoresistance. Moreover, non-specific proteasome inhibitors such as bortezomib can induce peripheral neuropathy and other toxicities that may compromise the ability to deliver therapy at full doses, thereby decreasing efficacy. One novel approach may be to target the immunoproteasome, a proteasomal variant found predominantly in cells of hematopoietic origin that differs from the constitutive proteasome found in most other cell types. Using purified preparations of constitutive and immunoproteasomes, we screened a rationally-designed series of peptidyl-aldehydes and identified several with relative specificity for the immunoproteasome. The most potent immunoproteasome-specific inhibitor, IPSI-001, preferentially targeted the  1i subunit of the immunoproteasome in vitro and in cellulo in a dose-dependent manner. This agent induced accumulation of ubiquitin-protein conjugates, pro-apoptotic proteins, and activated caspase-mediated apoptosis. IPSI-001 potently inhibited proliferation in myeloma patient samples and other hematologic malignancies. Importantly, IPSI-001 was able to overcome conventional and novel drug resistance, including resistance to bortezomib. These findings provide a rationale for the translation of IPSIs to the clinic, where they may provide anti-myeloma activity with greater specificity and less toxicity than current inhibitors.
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