Btk调控MDR1逆转急性淋巴细胞白血病耐药的研究  

Targeting Btk/MDR1 reverse multidrug resistance in acute lymphoblastic leukemia

作　　者：马晶晶[1] 邓媛[1] 张欣[1] 陶善东[1] 凌兰兰[1] 于亮[1,2] MA Jingjing;DENG Yuan;ZHANG Xin;TAO Shandong;LING Lanlan;YU Liang(Department of Hematology,the First People's Hospital of Huai'an Affiliated to Nanjing Medical University,Huai'an 223300,China;Hematology Laboratory of Nanjing Medical University,Nanjing 210029,China)

机构地区：[1]南京医科大学附属淮安第一医院血液科,江苏淮安223300 [2]南京医科大学血液病重点实验室,江苏南京210029

出　　处：《东南大学学报（医学版）》2019年第2期259-265,共7页Journal of Southeast University(Medical Science Edition)

基　　金：江苏省“333”工程科研资助立项项目(BRA2017243);淮安市科技计划项目-新型临床诊疗技术攻关项目(HAS201608);淮安市“533英才工程”和科研资助立项项目(HAA201739)

摘　　要：目的:通过观察Btk抑制剂依鲁替尼作用于急性淋巴细胞白血病(ALL)细胞株(Sup-B15)后细胞中MDR1mRNA、P-gp蛋白的表达及细胞对化疗药物敏感性的变化,探讨逆转ALL多药耐药的有效方法。方法:(1)利用依鲁替尼处理Sup-B15,PCR法检测处理后细胞中MDR1mRNA水平变化;免疫印迹法检测P-gp等蛋白水平变化;(2)利用化疗药物作用于依鲁替尼处理后的Sup-B15,CCK-8法检测细胞增殖。结果:(1)在Sup-B15中,依鲁替尼作用后的MDR1mRNA表达较对照组降低;细胞中P-gp等蛋白表达量较对照组降低。(2)依鲁替尼处理后的Sup-B15在相同Ara-C、ADR浓度作用下,其细胞增殖率较对照组降低(P<0.05)。结论:(1)依鲁替尼可降低Sup-B15中MDR1mRNA及P-gp蛋白的表达,其作用机制可能是通过抑制Btk、NFκB表达及生物学活性,从而抑制MDR1及P-gp的表达。(2)依鲁替尼增强ALL细胞对化疗药物的敏感性。Objective: By targeting Btk in acute lymphoblastic leukemia (ALL) cells, to observe the expression of MDR1 and P-gp and the changes of cellular sensitivity to chemotherapy drugs of ALL cells, to further explore the role of Btk in the regulation of ALL multidrug resistance. Methods:(1) Sup-B15 were treated with ibrutinib, and the mRNA and the protein expression levels of Btk and MDR1 (P-gp) were detected by PCR and Western blot, respectively.(2)Sup-B15 were first treated with ibrutinib, and then with Ara-C or ADR respectively, the cell proliferation was detected by CCK-8 method. Results:(1) After being treated with ibrutinib, the mRNA and protein expression levels of MDR1 and P-gp were decreased as compared with the control group.(2) When Sup-B15 were treated with ibrutinib and followed by Ara-C or ADR respectively, the cell proliferation rate was lower than that of the control group ( P <0.05). Conclusion:(1) Ibrutinib can decrease the expression of MDR1 mRNA and P-gp protein by inhibiting the expression of Btk and NFκB in ALL cells.(2) Ibrutinib can enhance the sensitivity of Sup-B15 cells to Ara-C and ADR.

关 键 词：急性淋巴细胞白血病 依鲁替尼 布鲁顿酪氨酸激酶 MDR1 P-糖蛋白 转录因子κB 多药耐药 

分 类 号：R733.71[医药卫生—肿瘤] R-33[医药卫生—临床医学]