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

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

Research output: Contribution to journalArticle

16 Scopus citations

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-kB 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. Mol Cancer Ther; 12(11); 2494-504.

Original languageEnglish (US)
Pages (from-to)2494-2504
Number of pages11
JournalMolecular cancer therapeutics
Volume12
Issue number11
StatePublished - Nov 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Zhang, L., Pham, L. V., Newberry, K. J., Ou, Z., Liang, R., Qian, J., Sun, L., Blonska, M., You, Y., Yang, J., Lin, X., Rollo, A., Tamayo, A. T., Lee, J., Ford, R. J., Zhao, X., Kwak, L. W., Yi, Q., & Wang, M. (2013). In vitro and in vivo therapeutic efficacy of carfilzomib in mantle cell lymphoma: Targeting the immunoproteasome. Molecular cancer therapeutics, 12(11), 2494-2504.