In vitro and in vivo therapeutic efficacy of carfilzomib in mantle cell lymphoma: targeting the immunoproteasome.

Abstract

Mantle cell lymphoma (MCL) remains incurable due to its inevitable pattern of relapse after treatment with current existing therapies. However, the promise of a cure for MCL lies in the burgeoning area of novel agents. In this study, we elucidated the therapeutic effect and mechanism of carfilzomib, a novel long-acting second-generation proteasome inhibitor, in MCL cells. We found that carfilzomib induced growth inhibition and apoptosis in both established MCL cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast, carfilzomib was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The carfilzomib-induced apoptosis of MCL cells was mediated by the activation of JNK, Bcl-2, and mitochondria-related pathways. In addition, carfilzomib inhibited the growth and survival signaling pathways NF-κB and STAT3. Interestingly, we discovered that expression of immunoproteasome (i-proteasome) subunits is required for the anti-MCL activity of carfilzomib in MCL cells. In MCL-bearing SCID mice/primary MCL-bearing SCID-hu mice, intravenous administration of 5 mg/kg carfilzomib on days 1 and 2 for 5 weeks slowed/abrogated tumor growth and significantly prolonged survival. Our preclinical data show that carfilzomib is a promising, potentially less toxic treatment for MCL. Furthermore, an intact i-proteasome, especially LMP2, appears to be necessary for its anti-MCL activity, suggesting that i-proteasome could serve as a biomarker for identifying patients who will benefit from carfilzomib.

• Authors: Liang Zhang, Lan V Pham, Kate J Newberry, Zhishuo Ou, Rong Liang, Jianfei Qian, Luhong Sun, Marzenna Blonska, Yun You, Jing Yang, Xin Lin, Alex Rollo, Archito T Tamayo, John Lee, Richard J Ford, Xiurong Zhao, Larry W Kwak, Qing Yi, Michael Wang
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 12 Issue 11 Pg. 2494-504 (Nov 2013) ISSN: 1538-8514 [Electronic] United States
• PMID: 23990113 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Antineoplastic Agents
• Oligopeptides
• carfilzomib
• Proteasome Endopeptidase Complex

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• Humans
• Lymphoma, Mantle-Cell (drug therapy, pathology)
• Male
• Mice
• Mice, SCID
• Mitochondria (metabolism)
• Molecular Targeted Therapy (methods)
• Oligopeptides (pharmacology, therapeutic use)
• Proteasome Endopeptidase Complex (genetics, metabolism)
• Signal Transduction (drug effects, genetics)