阿帕替尼逆转P-gp转运体介导的乳腺癌化疗多药耐药性的作用及其机制  

Reversal Effect of Apatinib on P-gp-mediated Multidrug Resistance of Human Breast Cancer and Its Mechanisms

作　　者：张圣村[1] 马敏[1] 徐丽丽[1] ZHANG Shengcun;MA Min;XU Lili(Department of Oncology, The Third Hospital of Ji ＇nan, Ji ＇nan 250132, China)

机构地区：[1]济南市第三人民医院肿瘤科,济南250132

出　　处：《肿瘤防治研究》2018年第4期210-214,共5页Cancer Research on Prevention and Treatment

摘　　要：目的探讨阿帕替尼对人乳腺癌化疗多药耐药性的逆转作用及其机制。方法不同浓度的阿帕替尼作用于体外培养的人乳腺癌MCF-7及MCF-7/ADR细胞48 h,MTT法检测阿帕替尼对两种细胞的细胞毒性;低毒浓度的阿帕替尼与化疗药物紫杉醇及阿霉素联用,探讨阿帕替尼对两种细胞化疗耐药性的影响;采用流式细胞术检测阿帕替尼对罗丹明123在MCF-7及MCF-7/ADR细胞内蓄积的影响;采用Pgp-Glo^(TM) Assay Systems试剂盒观察阿帕替尼对多药耐药相关蛋白P-gp的ATPase活性的影响;采用Western blot法检测阿帕替尼对P-gp表达及AKT磷酸化的影响。结果阿帕替尼可浓度依赖性地逆转乳腺癌MCF-7/ADR细胞对紫杉醇及阿霉素的多药耐药性(P<0.05)、增加罗丹明123在MCF-7/ADR细胞内的蓄积(P<0.05)及激活P-gp转运体的ATPase活性(P<0.05),而对P-gp的表达没有影响;此外,阿帕替尼不改变AKT的磷酸化水平。结论阿帕替尼可能通过抑制P-gp转运体的外排功能逆转P-gp转运体介导的乳腺癌化疗多药耐药性。Objective To investigate the reversal effect of apatinib on the multidrug resistance of human breast cancer and the underlying mechanisms. Methods MCF-7 and MCF-7/ADR cells were treated with different concentrations of apatinib for 48 h. Cell proliferation was measured by MTT assay. The reversal effect of apatinib on the multidrug resistance of MCF-7/ADR cells to paclitaxel and adriamycin were investigated by MTT assay. The effects of apatinib on the accumulation of rhodamine 123 in MCF-7 and MCF-7/ADR cells were investigated by flow cytometry. The effect of apatinib on ATPase activity of P-gp was investigated by Pgp-Glo？ Assay Systems. The effects of apatinib on the expression of P-gp, AKT and p-AKT were investigated by Western blot. Results Apatinib could reverse the multidrug resistance of MCF-7/ADR cells to paclitaxel and adriamycin, increase the accumulation of rhodamine 123 in MCF-7/ADR cells and the ATPase activity of P-gp in a concentration-dependent manner（P0.05）. Apatinib had no effect on the expression of P-gp or the phosphorylation of AKT. Conclusion Apatinib could reverse the P-gp-mediated multidrug resistance of human breast cancer cell line MCF-7/ADR by inhibiting the efflux function of P-gp.

关 键 词：阿帕替尼 乳腺癌 多药耐药性 P-糖蛋白 

分 类 号：R737.9[医药卫生—肿瘤]