title: 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.affiliation: Corresponding Authors: Liang Zhang, Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0903, Houston, TX 77030. liazhang@mdanderson.org.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Lan V
authors.initials: LV
authors.lastname: Pham
authors.forename: Kate J
authors.initials: KJ
authors.lastname: Newberry
authors.forename: Zhishuo
authors.initials: Z
authors.lastname: Ou
authors.forename: Rong
authors.initials: R
authors.lastname: Liang
authors.forename: Jianfei
authors.initials: J
authors.lastname: Qian
authors.forename: Luhong
authors.initials: L
authors.lastname: Sun
authors.forename: Marzenna
authors.initials: M
authors.lastname: Blonska
authors.forename: Yun
authors.initials: Y
authors.lastname: You
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: Alex
authors.initials: A
authors.lastname: Rollo
authors.forename: Archito T
authors.initials: AT
authors.lastname: Tamayo
authors.forename: John
authors.initials: J
authors.lastname: Lee
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ford
authors.forename: Xiurong
authors.initials: X
authors.lastname: Zhao
authors.forename: Larry W
authors.initials: LW
authors.lastname: Kwak
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism; D058990:Molecular Targeted Therapy / Q000379:methods*; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; C524865:carfilzomib; D046988:Proteasome Endopeptidase Complex