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

张圣村; 马敏; 徐丽丽

doi:10.3971/j.issn.1000-8578.2018.17.1112

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

摘要

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。

Abstract:
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 48h. 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^TM 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 (P < 0.05). 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.

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