Abstract
Background: Diffuse large B cell lymphoma (DLBCL) is a clinical and genetically heterogeneous lymphoid malignancy. Although the R-CHOP (rituximab plus cyclophosphamide, vincristine, doxorubicin, and prednisone) treatment can improve the survival rate of patients with DLBCL. However, more than 30% of patients exhibit treatment failure, relapse, or refractory disease. Therefore, novel drugs or targeted therapies are needed to improve the overall survival of patients with DLBCL. The compound DCZ0014 is a novel chemical similar to berberine, obtained by drug design and organic synthesis. Methods: The anti-DLBCL activity of DCZ0014 were investigated using assays of colony formation, CCK-8, TUNEL assay, EdU assay, cell cycle analysis, flow cytometry analysis, MMP analysis, Western blotting, immunohistochemistry and xenograft tumour model. Overexpression and knockdown of lyn in DLBCL cells was constructed with the small interfering RNAs or plasmid. The student's t-test was performed to the statistical analysis. Results: We found that DCZ0014 significantly inhibited the proliferation and activity of DLBCL cells, reduced the formation of their clones, and induced cell apoptosis. Following treatment with DCZ0014, DLBCL cells accumulated in G0/G1-phase of the cell cycle and showed decreased mitochondrial membrane potential. Additionally, DCZ0014 significantly inhibited DNA synthesis, enhanced DNA damage in DLBCL cells, as well as inhibited Lyn/Syk in B cell receptor signaling pathway. Further experiments demonstrated that DCZ0014 did not significantly affect peripheral blood mononuclear cells. In vivo analysis showed that DCZ0014 not only significantly inhibited tumor growth but also extended the survival time of mice in the DCZ0014-treated group. Conclusions: DCZ0014 showed potential for clinical application in the treatment of patients with DLBCL.
DCZ0014, a novel compound in the therapy of diffuse large B-cell lymphoma via the B cell receptor signaling pathway
