Ibrutinib inhibits microenvironment-mediated drug resistance in diffuse large B-cell lymphoma in vitro and in NOD/SCID mice
Ibrutinib,an irreversible Bruton”s tyrosine kinase inhibitor,induces significant clinical responses in B-cell malignancies.Our study aimed to elucidate ibrutinib”s actions on diffuse large B-cell lymphoma cells and microenvironment-mediated drug resistance.The actions of ibrutinib were analyzed in four DLBCL cell lines and primary cells by an MTS assay,an Annexin V-binding assay,Western blot,flow cytometry,ELISA,chemotaxis and adhesion assays,and clonogenic assays.In vivo study was performed in atumor-bearing NOD/SCID mouse xenograft model.First,we found that ibrutinib significantly inhibited BTK tyrosine phosphorylation and abrogated the constitutive activation of AKT and ERK1/2.On the other hand,ibrutinib inhibited the anti-apoptosis proteins Bcl-2,Bcl-xL,and Mcl-1 and then induced dose-dependent apoptosis by caspase-3 activation and poly ADP ribose polymerase cleavage.Furthermore,our results showed that ibrutinib combined with either the proteasome inhibitor bortezomib or the PI3Kδ inhibitor CAL-101 synergistically induced cytotoxicity in DLBCL cells.Of note,ibrutinib targeted the CXCL12/CXCR4 axis,significantly suppressed the adhesion and migration of DLBCL cells to mesenchymal stromal cells,and inhibited clonogenicity and MSC-mediated drug resistance.In vivo studies showed that ibrutinib inhibited tumor growth in tumor-bearing xenograft mice.Ibrutinib displayed a dual mechanism of action against DLBCL,which not only inhibited BCR-dependent growth signals but also targeted the CXCL12/CXCR4 axis and suppressed MSC-mediated clonogenicity and drug resistance.Ibrutinib as a single agent and in combination with CAL-101 or bortezomib could be a novel modality for the treatment of DLBCL.
Bruton”s tyrosine kinase ibrutinib B-cell receptor signaling microenvironment CXCL-12/CXCR4
Bing Xia Fulian Qu Xiaowu Li Shanqi Guo Fang Li Xin Jin Chen Tian Yong Yu Yafei Wang Yizhuo Zhang
Department of Hematology,Tianjin Medical University Cancer Institute and Hospital,National Clinical Research Center for Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin,300060,PR China
国内会议
中国老年学和老年医学学会老年肿瘤分会年会暨第十届中国老年肿瘤学大会
北京
英文
236-248
2016-04-08（万方平台首次上网日期，不代表论文的发表时间）