Ibrutinib抑制弥漫大B细胞淋巴瘤细胞生存的作用研究

发布时间：2018-06-26 05:48

本文选题：弥漫大B细胞淋巴瘤 + ibrutinib　；参考：《中国肿瘤临床》2017年18期

【摘要】：目的:探讨Bruton酪氨酸激酶(Bruton's tyrosine kinase,BTK)抑制剂ibrutinib抑制弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)细胞生存的作用及其相关机制。方法:用不同浓度的ibrutinib处理DLBCL细胞系SUDHL-10、HBL-1和患者原代细胞,以MTT法检测细胞的增殖抑制情况;以Annexin V/PI流式细胞术和DAPI染色法检测细胞的凋亡情况;应用Western blot法检测细胞表达磷酸化BTK、AKT、ERK的变化。DLBCL细胞与MSC共培养后,体外克隆形成实验和NOD/SCID肿瘤模型小鼠检测ibrutinib在肿瘤微环境里对DLBCL细胞的抑制作用。结果:2.5μmol/L及更高浓度的ibrutinib对DLBCL细胞的增殖有明显的抑制作用,且呈剂量依赖性。1.0、2.5μmol/L ibrutinib作用于SUDHL-10细胞24 h,细胞凋亡率分别为(21.73±3.64)%和(34.71±2.36)%,高于对照组(3.55±1.89)%(P0.05)。5、10μmol/L ibrutinib处理24 h后,DLBCL细胞系均出现核皱缩(5μmol/L)、碎裂(10μmol/L)。ibrutinib处理细胞后磷酸化BTK、AKT、ERK的表达均明显降低。ibrutinib抑制共培养时DLBCL细胞的体外克隆形成(P0.01)及DLBCL细胞在体内的增殖生长,差异均具有统计学意义(P0.05)。结论:ibrutinib可抑制细胞系SUDHL-10和HBL-1的增殖,诱导凋亡,其机制可能通过阻断AKT、ERK信号途径而实现;在肿瘤微环境中ibrutinib同样对DLBCL细胞具有较强的抑制生存的作用,该药物有望为DLBCL的治疗带来希望。
[Abstract]:Aim: to investigate the inhibitory effect of ibrutinib, an inhibitor of Bruton tyrosine kinase, on the survival of diffuse large B-cell lymphoma (diffuse large B cell lymphoma DLBCL) cells and its related mechanisms. Methods: DLBCL cell line SUDHL-10 HBL-1 and primary cell line were treated with different concentrations of ibrutinib. The proliferation inhibition was detected by MTT assay, and apoptosis was detected by Annexin V / Pi flow cytometry and DAPI staining. DLBCL cells were co-cultured with MSC by Western blot assay to detect the expression of phosphorylated BTKK Akton-ERK. The clone formation test in vitro and the inhibitory effect of ibrutinib on DLBCL cells in tumor microenvironment in NOD / SCID model mice were detected. Results: the proliferation of DLBCL cells was inhibited by 2. 5 渭 mol / L and higher concentrations of ibrutinib. The apoptotic rate of SUDHL-10 cells was (21.73 卤3.64)% and (34.71 卤2.36) in a dose-dependent manner, which was higher than that in the control group (3.55 卤1.89)% (P0.05) .510 渭 mol / L ibrutinib for 24 h. Nuclear shrinkage (5 渭 mol / L) was observed in DLBCL cell lines treated with 10 渭 mol / L ibrutinib, and the expression of phosphorylated AKKTERK was significantly decreased after treatment with fragmentation (10 渭 mol / L) .ibrutinib (10 渭 mol / L). Ibrutinib inhibited the formation of DLBCL cells in vitro (P0.01) and the proliferation and growth of DLBCL cells in vivo. The difference was statistically significant (P0.05). Conclusion the cell line SUDHL-10 and HBL-1 can be inhibited and apoptosis induced by the cell line SUDHL-10 and HBL-1. The mechanism may be achieved by blocking the signal pathway of AKTU ERK, and ibrutinib can also inhibit the survival of SUDHL-10 cells in tumor microenvironment. The drug is expected to provide hope for the treatment of DLBCL.
【作者单位】：天津医科大学肿瘤医院血液科国家肿瘤临床医学研究中心天津市肿瘤防治重点实验室天津市恶性肿瘤临床医学研究中心;
【基金】：国家自然科学基金项目(编号:81600163、81570201)资助~~
【分类号】：R733.1

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