Bruton’s Tyrosine Kinase Inhibitor PCI-32765 In The Treatment Of Aggressive B Cell Lymphoma And Its Action Mechanism

Background and objective:With the rapid development of the medical career,the great progress has been made from traditional chemotherapy to molecularly targeted therapy for the treatment of aggressive B-cell malignancies.In recent years,some pre-clinical studies and clinical trials have showed that PCI-32765,a selective,irreversible Bruton’s tyrosine kinase(BTK)inhibitor,is a novel,molecularly targeted agent for patients with B-cell malignancies,can selectively combine with the BTK,which is a necessary component of the B cell antigen receptor signaling pathway,thus blocking receptor signaling,caused apoptosis in malignant B cells,and inhibit the migration and adhesion.Currently,study of PCI-32765 is only limited to chronic lymphocytic leukemia,while the role in aggressive B-cell lymphoma is not clear.The purpose of this study is to observe the role of Bruton’s tyrosine kinase(BTK)inhibitor PCI-32765 in aggressive B-cell lymphoma cell lines in vitro(Raji,Jeko-1,SUDHL-10 and HBL-2),and further study the mechanisms concerned.Methods:Cell viability was evaluated by MTS assays,and Annexin V/PI assays and DAPI staining were used to evaluate cell apoptosis both in B cell lines.Western blot analysis was employed to explore the possible mechanisms.Results:MTT assay indicated that Bruton’s tyrosine kinase(BTK)inhibitor PCI-32765 could inhibit aggressive B-cell lymphoma proliferation in dose dependent manner.Flow cytometry analysis showed that compared with control group,with the concentration of PCI-32765 increased,the percentage of cells in apoptosis phase was increased gradually.Western blot analysis showed that compared with control group,with the concentration of PCI-32765 increased,cell protein phosphorylation levels of BTK and ERK1/2 was downregulated,suggesting that drug inhibition of proliferation and induce apoptosis were probably connected with the BCR and Ras/MAPK pathway.Conclusion:Bruton’s tyrosine kinase(BTK)inhibitor PCI-32765 can effectively suppress aggressive B-cell lymphoma proliferation and induce apoptosis in concentration-dependent manner;the mechanism of action was probably connected with the BCR and Ras/MAPK pathway.