Total Saponins from Paris forrestii Reverse Multidrug Resistance of MCF-7/ADM Cells by Suppression of P-gp via ERK Signaling Pathway

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 µg/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.