Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
CAS Key Laboratory of Receptor Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Neoplasia. 2022 Jan;24(1):50-61. doi: 10.1016/j.neo.2021.12.001. Epub 2021 Dec 7.
Diffuse large B cell lymphoma (DLBCL) is a clinical and genetically heterogeneous lymphoid malignancy. Although R-CHOP (rituximab plus cyclophosphamide, vincristine, doxorubicin, and prednisone) treatment can improve the survival rate of patients with DLBCL, more than 30% of patients exhibit treatment failure, relapse, or refractory disease. Therefore, novel drugs or targeted therapies are needed to improve the survival of patients with DLBCL. The compound DCZ0014 is a novel chemical similar to berberine. In this study, we found that DCZ0014 significantly inhibited the proliferation and activity of DLBCL cells, 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 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. Tumor xenograft model showed that DCZ0014 not only inhibited tumor growth but also extended the survival time of mice. Thus, DCZ0014 showed potential for clinical application in the treatment of patients with DLBCL.
弥漫性大 B 细胞淋巴瘤（DLBCL）是一种临床和遗传上具有异质性的淋巴恶性肿瘤。尽管 R-CHOP（利妥昔单抗联合环磷酰胺、长春新碱、多柔比星和泼尼松）治疗可以提高 DLBCL 患者的生存率，但仍有 30%以上的患者出现治疗失败、复发或耐药。因此，需要新的药物或靶向治疗来改善 DLBCL 患者的生存。化合物 DCZ0014 是一种类似于小檗碱的新型化学物质。在这项研究中，我们发现 DCZ0014 可显著抑制 DLBCL 细胞的增殖和活性，并诱导细胞凋亡。用 DCZ0014 处理后，DLBCL 细胞在细胞周期的 G0/G1 期积累，线粒体膜电位降低。此外，DCZ0014 抑制 DNA 合成，增强 DLBCL 细胞的 DNA 损伤，并抑制 B 细胞受体信号通路中的 Lyn/Syk。进一步的实验表明，DCZ0014 对外周血单核细胞没有明显影响。肿瘤异种移植模型表明，DCZ0014 不仅抑制肿瘤生长，还延长了小鼠的生存时间。因此，DCZ0014 在治疗 DLBCL 患者方面具有临床应用潜力。
