Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical 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, Robert Z. Orlowski

Research output: Contribution to journalArticle

508 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3281-3290
Number of pages10
JournalBlood
Volume110
Issue number9
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

Fingerprint

Proteasome Inhibitors
Proteasome Endopeptidase Complex
Ubiquitin
Multiple Myeloma
Cell death
Cell Death
Chemical activation
Apoptosis
JNK Mitogen-Activated Protein Kinases
Depolarization
Chymotrypsin
Mitochondrial Membranes
Hematologic Neoplasms
Caspases
Cytochromes c
Refractory materials
Dexamethasone
Cells
Bortezomib
carfilzomib

ASJC Scopus subject areas

  • Hematology

Cite this

Kuhn, D. J., Chen, Q., Voorhees, P. M., Strader, J. S., Shenk, K. D., Sun, C. M., ... Orlowski, R. Z. (2007). Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood, 110(9), 3281-3290. https://doi.org/10.1182/blood-2007-01-065888

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

In: Blood, Vol. 110, No. 9, 01.11.2007, p. 3281-3290.

Research output: Contribution to journalArticle

Kuhn, DJ, Chen, Q, Voorhees, PM, Strader, JS, Shenk, KD, Sun, CM, Demo, SD, Bennett, MK, Van Leeuwen, FWB, Chanan Khan, AA & Orlowski, RZ 2007, 'Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma', Blood, vol. 110, no. 9, pp. 3281-3290. https://doi.org/10.1182/blood-2007-01-065888
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. / Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. In: Blood. 2007 ; Vol. 110, No. 9. pp. 3281-3290.
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abstract = "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.",
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