Ceritinib增强ABCB1过表达白血病多药耐药的作用及机制研究

Role and mechanism of Ceritinib’s enhancement of drug resistance in ABCB1 overexpression leukemia

目的研究色瑞替尼(Ceritinib)增强ABCB1过表达白血病多药耐药的作用及机制。方法采集白血病骨髓样本,白血病细胞的分离、复苏及冻存,测定细胞毒性,然后建立裸鼠成瘤模型,检测Ceritinib联合阿霉素对小鼠肿瘤的抑制作用,阐明Ceritinib逆转耐药。结果Ceritinib能够浓度依赖性降低K562/adr细胞阿霉素和紫杉醇的IC50值,即增加其对细胞的毒性作用,但是Ceritinib却未改变顺铂(不是ABCB1底物的)的细胞毒性。生理盐水组、Ceritinib组、阿霉素组裸鼠的肿瘤体积比较差异无统计学意义(P>0.05);Ceritinib联合阿霉素组的肿瘤体积小于生理盐水组、Ceritinib组、阿霉素组,差异有统计学意义(P<0.05);Ceritinib联合阿霉素组肿瘤平均重量(0.89±0.29)g低于生理盐水组的(2.32±0.31)g、Ceritinib组的(2.18±0.28)g和阿霉素组的(2.19±0.56)g,差异有统计学意义(P<0.05)。结论Ceritinib可以增强ABCB1过表达白血病细胞化疗药物的疗效,为新型多药耐药(MDR)调节剂的开发提供策略。

Objective To study the role and mechanism of Ceritinib’s enhancement of drug resistance in ABCB1 overexpression leukemia.Methods Bone marrow samples of leukemia were collected for isolation,resuscitation and cryopreservation of leukemia cells,and the cytotoxicity was determined.Then the tumor model of nude mice was established to detect the inhibitory effect of Ceritinib combined with adriamycin on tumor in mice,and to clarify the reversal of drug resistance by Ceritinib.Results Ceritinib could decrease the IC50 value of adriamycin and paclitaxel in K562/adr cells in a concentration-dependent manner,that is to say,it could increase their toxic effects on cells,but Ceritinib did not change the cytotoxicity of cisplatin(not the substrate of ABCB1).There was no statistically significant difference in tumor volume in nude mice of the normal saline group,Ceritinib group,and adriamycin group(P>0.05).The tumor volume in the Ceritinib combined with adriamycin group was smaller than that of the normal saline group,Ceritinib group,and adriamycin group,and the difference was statistically significant(P<0.05).The mean tumor weight(0.89±0.29)g in the Ceritinib combined with adriamycin group was lower than(2.32±0.31)g in the normal saline group,(2.18±0.28)g in the Ceritinib group and(2.19±0.56)g in the adriamycin group,and the difference was Statistically significant(P<0.05).Conclusion Ceritinib can enhance the therapeutic effect of ABCB1 overexpression leukemia cells and provide strategies for the development of new multidrug resistance(MDR)modulators.