Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma

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 resi...

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Bibliographic Details
Published in:Blood 2007-11, Vol.110 (9), p.3281-3290
Main Authors: Kuhn, Deborah J., Chen, Qing, Voorhees, Peter M., Strader, John S., Shenk, Kevin D., Sun, Congcong M., Demo, Susan D., Bennett, Mark K., van Leeuwen, Fijs W.B., Chanan-Khan, Asher A., Orlowski, Robert Z.
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis - drug effects
Biological and medical sciences
Boronic Acids - pharmacology
Bortezomib
Cell Proliferation - drug effects
Drug Evaluation, Preclinical
Drug Resistance, Neoplasm - drug effects
General aspects
Humans
Immunodeficiencies. Immunoglobulinopathies
Immunoglobulinopathies
Immunopathology
Medical sciences
Models, Biological
Multiple Myeloma - drug therapy
Multiple Myeloma - pathology
Neoplasia
Oligopeptides - pharmacology
Oligopeptides - therapeutic use
Pharmacology. Drug treatments
Protease Inhibitors - pharmacology
Protease Inhibitors - therapeutic use
Proteasome Inhibitors
Pyrazines - pharmacology
Signal Transduction - drug effects
Tumor Cells, Cultured
Ubiquitin - antagonists & inhibitors
Ubiquitin - metabolism
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2007-01-065888