title: Carfilzomib Inhibits Constitutive NF-κB Activation in Mantle Cell Lymphoma B Cells and Leads to the Induction of Apoptosis.
abstract: Mantle cell lymphoma (MCL) remains incurable and new treatments are needed, especially in the relapsed/refractory setting. We therefore investigated the effects of carfilzomib, a novel, long-acting, second-generation proteasome inhibitor, in MCL cells. Eight established MCL cell lines and freshly isolated primary MCL cells were treated with carfilzomib. Cell proliferation was assessed by a 3H-thymidine incorporation assay. Cell apoptosis was evaluated by flow cytometry with annexin V and propidium iodide. Electrophoresis mobility shift (EMSA), Western blot, and luciferase assays were used to analyze NF-κB activation and related signaling proteins. Carfilzomib inhibited growth and induced 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 occurred in a caspase-dependent manner through both intrinsic and extrinsic caspase pathways. In addition, carfilzomib inhibited constitutive activation of the NF-κB signaling cascade, both in MCL cell lines and primary MCL cells, by completely blocking the phosphorylation of IκBα. Our results demonstrate that carfilzomib can induce growth arrest and apoptosis in MCL cells and that the mechanism may involve the NF-κB signaling pathway.
authors.affiliation: Department of Emergency Surgery, Zhongshan Hospital, Xiamen University, Fujian Medical University Clinic Teaching Hospital, Xiamen, China.
authors.forename: Yong-Li
authors.initials: YL
authors.lastname: Zhang
authors.forename: Matthew Ho Zhi
authors.initials: MH
authors.lastname: Guang
authors.forename: Hui-Qin
authors.initials: HQ
authors.lastname: Zhuo
authors.forename: Xiang-Hui
authors.initials: XH
authors.lastname: Min
authors.forename: Qin
authors.initials: Q
authors.lastname: Yao
authors.forename: Ai-Qi
authors.initials: AQ
authors.lastname: Gu
authors.forename: Sheng-Hua
authors.initials: SH
authors.lastname: Wu
authors.forename: Dai-Bo
authors.initials: DB
authors.lastname: Zhang
authors.forename: Jing-Yuan
authors.initials: JY
authors.lastname: Lu
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Chen
authors.forename: Ke-Jie
authors.initials: KJ
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016328:NF-kappa B; D009363:Neoplasm Proteins; D009842:Oligopeptides; C524865:carfilzomib