Combined Treatment withEpimedium koreanumNakai Extract and Gefitinib Overcomes Drug Resistance Caused by T790M Mutation in Non-Small Cell Lung Cancer Cells

Abstract

Although the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib, have shown promising therapeutic efficacy in nonsmall cell lung cancer (NSCLC) patients harboring EGFR activating mutation, development of acquired resistance is almost inevitable. We investigated whether the addition of Epimedium koreanum Nakai extract (EEF) to gefitinib could overcome the resistance of NSCLC cells to gefitinib. In our study, the growth inhibitory effects of cotreatment differed between mutant EGFR and wild type EGFR. A synergistic antiproliferative effect was observed in the combined treatments in H1975 and PC-9GR cells carrying T790M EGFR. In addition, the cotreatment exhibited a much greater inhibition than either agent alone on the following metastatic processes: (a) invasion, (b) wound healing, and (c) tubule formation by endothelial cells. The phosphorylations of EGFR family (EGFR, HER-2, and HER-3) and EGFR downstream PI3K/Akt/mTOR pathway in H1975 and PC-9/GR cells were also attanuated, whereas EEF or gefitinib alone had no obvious effects. Similarly, the combination effectively suppressed tumor growth and increased mice survival in PC-9GR xenografts. The results indicate that the addition of EEF to gefitinib is a promising strategy to overcome T790M-mediated drug resistance.

Digoxin Suppresses Tumor Malignancy through Inhibiting Multiple Src-Related Signaling Pathways in Non-Small Cell Lung Cancer

“…NSCLC patients with an Arg substitution for Leu at position 858 or a deletion of exon 19 in EGFR are responsive to EGFR TKIs [ 38 ]. Several clinical studies have indicated that the amplification of a T790M mutation in EGFR contributes to the acquisition of EGFR TKI resistance [ 39 ]. Therefore, TKI-sensitive lung cancer cell lines (PC9, exon 19 deletion; H3255, L858R EGFR mutant) [ 40 ] and TKI-resistant lung cancer cell lines (PC9/gef, exon 19 deletion, acquired resistance; H1975, L858R/T790M EGFR mutant) [ 38 ] were used to evaluate the anticancer effectiveness of digoxin.…”

Icariside II inhibits the EMT of NSCLC cells in inflammatory microenvironment via down-regulation of Akt/NF-κB signaling pathway

“…In vitro scratch‐wound analysis was performed as previously described . After scratched with a 200 µl pipette tip, the wounded cultures of A549 or H1299 monolayers were rinsed twice with PBS to eliminate non‐adherent cells and further treated for 24 h, as indicated.…”

“…Nuclear protein was isolated using the Nuclear Extraction Kit (Keygen Biotech, Nanjing, China). Antibodies against E‐cadherin, N‐cadherin, vimentin, GSK‐3β, phospho‐GSK‐3β, phospho‐Akt, phospho‐Akt, NF‐κB p65, phosphorylated p65, AP‐1, IκBα, phosphorylated IκBα, Lamin A (Santa Cruz, CA), Slug, Snail, phospho‐ERK1/2, ERK1/2, β‐actin (Cell Signaling Technology, Danvers, MA) were used to detect protein levels by Western blot analysis, as described previously . The signal was detected using an enhanced chemiluminescence kit (Boster, Wuhan, China).…”

Preparation and antitumor evaluation of self-assembling oleanolic acid-loaded Pluronic P105/D-α-tocopheryl polyethylene glycol succinate mixed micelles for non-small-cell lung cancer treatment

“…A549 cells were cultured in high-glucose DMEM, supplemented with 10% FBS, at 37°C in a 5% CO 2 atmosphere. 16 The medium was changed every other day. When the cells reached 90% confluence, they were trypsinized with 0.25% trypsin-EDTA and subcultured.…”