Total Saponins from Paris forrestii Reverse Multidrug Resistance of MCF-7/ADM Cells by Suppression of P-gp via ERK Signaling Pathway
Total Saponins from Paris forrestii Reverse Multidrug Resistance of MCF-7/ADM Cells by Suppression of P-gp via ERK Signaling Pathway
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DOI：
10.1248/bpb.b20-00014
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发表时间：
2020-12-01
影响因子：
2
通讯作者：
Zhou, Yiping
中科院分区：
文献类型：
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作者：
Chai, Dongya;Yuan, Jiaqi;Zhou, Yiping
我们前期的研究表明，鸢尾总皂苷（PCT3）对阿霉素耐药人乳腺腺癌细胞（MCF-7/ADM）的增殖有明显的抑制作用，且这种抑制作用明显强于亲本细胞（MCF-7）。本研究旨在检测PCT3对MCF-7/ADM细胞的逆转作用，并了解其作用机制。结果表明，低浓度PCT3（0.3、1和3 μ g/mL）可逆转MCF-7/ADM细胞对ADM、顺铂（DDP）和5-氟尿嘧啶（5-FU）的耐药性，ADM的逆转倍数分别为16.4、19.5和31.7倍，DDP的逆转倍数为1.6、1.4和1.4倍，5-FU的逆转倍数分别为1.7、1.8和5.6倍。此外，PCT3显著增加了MCF-7/ADM细胞中ADM和Rhodamine 123 （Rh123）的积累，提示PCT3可能通过影响MDR1基因编码的药物外排泵p -糖蛋白（P-gp）的功能起作用。PCT3处理后MDR1基因和P-gp蛋白表达均下调。进一步的结果表明，p38丝裂原活化蛋白激酶（MAPK）和细胞外信号调节激酶（ERK）通路在MCF-7/ADM细胞中显著激活，抑制p38或ERK可减弱P-gp的表达。而PCT3只下调了ERK的磷酸化水平，说明PCT3通过抑制ERK信号通路使P-gp过表达的MCF-7/ADM细胞对ADM敏感。
Our previous study demonstrated that the total saponins from Paris forristii (PCT3) had obvious inhibitory effect on the proliferation of adriamycin-resistant human breast adenocarcinoma cells (MCF-7/ADM), and this effect was significantly stronger than that in parental cells (MCF-7). This study was designed to test the reversal effect of PCT3 on MCF-7/ADM cells and to understand its mechanism of action. Results demonstrated that low cytotoxic concentrations of PCT3 (0.3, 1 and 3 mu g/mL) reversed resistance of MCF-7/ADM cells to ADM, cisplatin ( DDP) and 5-fluorouracil (5-FU), with reversal fold of 16.4, 19.5 and 31.7 for ADM, 1.6, 1.4 and 1.4 for DDP, 1.7, 1.8 and 5.6 for 5-FU, respectively. Moreover, PCT3 significantly increased the accumulation of ADM and Rhodamine 123 (Rh123) in MCF-7/ADM cells, suggesting that PCT3 may act by affecting the function of drug efflux pump P-glycoprotein (P-gp), which is encoded by MDR1 gene. Both MDR1 gene and P-gp protein expression was downregulated by PCT3 treatment. Further results demonstrated that p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) pathway was remarkably activated in MCF-7/ADM cells, inhibition of p38 or ERK attenuated P-gp expression. While, only the phosphorylation level of ERK was downregulated by PCT3, indicating that PCT3 sensitized P-gp overexpressed MCF-7/ADM cells to ADM via inhibition of ERK signaling pathway.