Abstract
BackgroundAlthough rituximab in the combination of CHOP chemotherapy has been widely used as the standard treatment for several kinds of B-cell non-Hodgkin lymphoma (B-NHL), a great number of B-NHL patients treated with this immunotherapy still develop primary and secondary resistance. Recently Bruton’s tyrosine kinase (Btk) inhibitor ibrutinib showed promising therapeutic effect in relapsed/refractory CLL and B-cell NHL, which provided essential alternatives for these patients.MethodsThe proliferation and apoptosis induction of tumor cells were measured by cell viability assay and Annexin-V staining. Western Blotting analysis and real-time PCR were used to detect the expression level of target proteins and chemokines production.ResultsWe demonstrated that ibrutinib inhibited the proliferation and induced apoptosis of GCB-DLBCL cell lines through suppression of BCR signaling pathway and activation of caspase-3. Furthermore, the chemokines CCL3 and CCL4 production from tumor cells were also found to be attenuated by ibrutinib treatment. But different cell lines exhibited distinct sensitivity after ibrutinib treatment. Interestingly, the decreasing level of p-ERK after ibrutinib treatment, but not the basal expression level of Btk, correlated with different drug sensitivity.ConclusionsIbrutinib could be a potentially useful therapy for GCB-DLBCL and the decreasing level of p-ERK could become a useful biomarker to predict related therapeutic response.
Highlights
Diffuse large B cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma (NHL) with aggressive property could be divided into three subgroups based on gene expression profile: germinal centre B celllike DLBCL (GCB-DLBCL), activated B cell-like DLBCL (ABC-DLBCL) and primary mediastinal B cell lymphoma [1,2]
Ibrutinib inhibited the proliferation of GCB-DLBCL cell lines in a dose- and time-dependent manner Firstly, we investigated the anti-tumor effects of ibrutinib in GCB-DLBCL cell lines SU-DHL-16 and OCI-Ly7
Ibrutinib induced cell apoptosis in GCB-DLBCL cell lines by caspase dependent pathway To further investigate the mechanisms involved in anti-proliferation process by ibrutinib, Annexin-V and PI staining apoptotic cells were analyzed by flow cytometry
Summary
Diffuse large B cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma (NHL) with aggressive property could be divided into three subgroups based on gene expression profile: germinal centre B celllike DLBCL (GCB-DLBCL), activated B cell-like DLBCL (ABC-DLBCL) and primary mediastinal B cell lymphoma [1,2]. B cell antigen receptor (BCR) signaling pathway has been recognized essential for the development of normal B cell and pathogenesis of B cell malignancies [5,6,7,8]. Bruton tyrosine kinase (Btk), a crucial regulator within the BCR signaling pathway, belongs to non-receptor tyrosine kinase of Tec family that expressed in many hematopoietic lineages [9]. Targeting small molecules within BCR signaling pathway, especially Btk inhibition would be a novel approach for treating B cell lymphomas. Rituximab in the combination of CHOP chemotherapy has been widely used as the standard treatment for several kinds of B-cell non-Hodgkin lymphoma (B-NHL), a great number of B-NHL patients treated with this immunotherapy still develop primary and secondary resistance. Bruton’s tyrosine kinase (Btk) inhibitor ibrutinib showed promising therapeutic effect in relapsed/refractory CLL and B-cell NHL, which provided essential alternatives for these patients
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