Ibrutinib逆转SDF-1α/CXCR4介导的急性淋巴细胞白血病耐药机制  

SDF-1α/CXCR4 Mediated Drug Resistance Can be Reversed by Ibrutinib in Acute Lymphoblastic Leukemia

作　　者：胡媛媛[1] 陶善东[1] 马晶晶[1] 周立涛[1] 陈月[1] 于亮[1] 

机构地区：[1]南京医科大学附属淮安第一医院血液科

出　　处：《中国实验血液学杂志》2017年第3期754-760,共7页Journal of Experimental Hematology

摘　　要：目的:探讨在急性淋巴细胞白血病细胞株SUP-B15中Ibrutinib对SDF-1α/CXCR4轴介导的耐药影响。方法:流式细胞术检测细胞凋亡及细胞表面CXCR4表达情况,Western blot检测CXCR4、ERK、Bcl-xL表达水平,qPCR检测CXCR4的mRNA表达水平。结果:Ibrutinib增强化疗药物阿霉素诱导SUP-B15的凋亡(17.100%±4.3%vs28.133%±3.16%);Ibrutinib抑制SDF-1α诱导的CXCR4磷酸化,呈浓度和时间依赖性(r_(24h)=-0.99659,r_(48h)=-0.99764,r=-0.99980);Ibrutinib抑制CXCR4下游信号分子ERK、BCL-xL的表达与活性。结论:Ibrutinib增强SUP-B5细胞株对化疗药物阿霉素的敏感性,逆转SDF-1α/CXCR4轴介导的耐药,其可能的作用机制是通过抑制CXCR4/ERK/BCL-xL信号通路而实现的。Objective： To explore the effect of Ibrutinib on the chemoresistance mediated by SDF-la/CXCR4 axis in ALL cells. Methods ： Flow cytometry was used to detect the apoptosis of cell line and expression of surface membrane CXCR4, Western blot was used to determine the expression level of CXCR4, ERK and Bcl-xL proteins, qPCR was used to assay the mRNA level of CXCR4. Results： Ibrutinib enhanced the apoptosis induced by adriamycin（ADR） （17. 100 ±4.3% to 28. 133 ± 3.16% ） ; Ibrutinib inhibited the phosphorylation of CXCR4 induced by SDF-la and with concen- tration- and time- dependent manner （ r24h = - 0. 99659, r48h = - 0. 99764, r = - 0. 99980）. Ibrutinib inhibited the ex- pression and activity of CXCR4 downstream signaling molecules pERK and BCL-xL. Conclusion： Ibrutinib can enhance the sensitivity of SUP-B15 to ADR, reverse SDF-1a/CXCR4-mediated chemoresistance in Ph ＋ acute lymphoblastic leu- kemia cells. This mechanism of ibrutinib may be assosiated with inhibiting CXCR4/ERK/BCL-xL.

关 键 词：急性淋巴细胞白血病 Ibrutinib 基质细胞衍生因子-1 CXCR4 耐药 

分 类 号：R733.71[医药卫生—肿瘤]