Paris saponin VII enhanced the sensitivity of HepG2/ADR cells to ADR via modulation of PI3K/AKT/MAPK signaling pathway

To find the effect of Paris saponin VII (PS VII)-mediated PI3K/AKT/MAPK signaling pathway on the sensitivity of ADR-resistant HepG2 cell (HepG2/ADR) cells to ADR. The proliferation inhibitory rates were detected by using MTT assay. Flow cytometry was employed to examine the intracellular accumulation of ADR. The expressions of drug-resistant genes (P-gp, MRP and BCRP) were detected by qRT-PCR, cell apoptosis by Annexin-V-FITC/PI staining, and the expressions of drug-resistance-related proteins, apoptosis-related proteins, and PI3K/AKT/MAPK pathway-related proteins were determined by Western blotting. HepG2/ADR and HepG2 cells treated with PS VII (0.88, 1.32, 1.98, and 2.97 μM) for 48 hours showed increased proliferation inhibitory rate in a dose-dependent manner. HepG2/ADR cells treated PS VII (0.88, 1.32, 1.98 μM) for 48 hours showed decreased IC50 of ADR. Compared with HepG2/ADR cells treated with ADR (5 nM), those treated with PS VII (≤1.98 μM) and ADR (5 nM) showed enhanced ADR accumulation, decreased drug-resistant gene expressions, increased cell apoptosis with unregulated Bax and cleaved caspase-3 and downregulated Bcl-2, as well as the inhibition of PI3K/AKT/MAPK pathway. Moreover, the combination of ADR (5 nM), PS VII (1.98 μM), and LY294002 (PI3K/AKT inhibitor, 20 μM)/SB203580 (P38 inhibitor, 20 μM) for 48 hours could further decreased the HepG2/ADR cell viability, but induced cell apoptosis, accompanying with the decreased expressions of drug-resistant genes. PS VII could downregulate the expressions of drug-resistance genes, increase intracellular accumulation of ADR, promote cell apoptosis, and enhance the sensitivity of HepG2/ADR cells to ADR via PI3K/AKT/MAPK.