Gefitinib Combined with Pemetrexed Affects Proliferation and Apoptosis of Non-Small Cell Lung Cancer Cells by Regulating PI3KAKT Pathway

Abstract

Dysfunction of PI3K/AKT pathway mediates EGFR-TKI resistance, which can be corrected by chemotherapy combined with EGFR-TKI. Pemetrexed mediates PI1K/AKT activity, thus modulating cell proliferation and apoptosis. This study investigated if Gefitinib combined with Pemetrexed played a role in regulating PI3K/AKT pathway and proliferation/apoptosis of non-small cell lung cancer (NSCLC). IC50 and p-AKT expression were compared between Gefitinib and Pemetrexed on PC9 or H1975 cells. H1975 cells were treated with Gefitinib and/or Pemetrexed, for assay of apoptosis and proliferation by flow cytometry. H1975 cells were infused into nude mice, which were treated with Gefitinib and/or Pemetrexed. Tumor growth was compared, along with p-AKT, Sur-vivin, and Ki67 expression. Gefitinib had 1.43 μM and 12.26 μM IC50 in PC9 and H1975 cells, whilst Pemetrexed had IC50 values of 0.81 μM and 1.32 μM. Gefitinib-resistant H1975 cells had significantly higher p-AKT than drug sensitive PC9 cells. Pemetrexed had more potent effect for anti-proliferation, pro-apoptosis, and down-regulation of p-AKT or Survivin than Gefitinib. Combined therapy remarkably weakened Gefitinib resistance in H1975 cell, and exerted more potent inhibitory effects on tumor growth in nude mice, accompanied with PI3K/ATK inactivation and Ki67 down-regulation. Pemetrexed combined with Gefitinib inhibits lung cancer cell H1975 proliferation and facilitates cell apoptosis via suppressing PI3K/AKT signal pathway, thus weakening Gefitinib resistance of lung cancer cells.