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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.