title: Combined treatment with Epimedium koreanum Nakai 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.
authors.affiliation: a Key Laboratory of Delivery Systems of Chinese Meteria Medica , Jiangsu Provincial Academy of Chinese Medicine , Jiangsu , Nanjing , China.
authors.forename: Jie
authors.initials: J
authors.lastname: Song
authors.forename: Rongling
authors.initials: R
authors.lastname: Zhong
authors.forename: Houcai
authors.initials: H
authors.lastname: Huang
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Zhang
authors.forename: Dongmei
authors.initials: D
authors.lastname: Ding
authors.forename: Hongmei
authors.initials: H
authors.lastname: Yan
authors.forename: E
authors.initials: E
authors.lastname: Sun
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Jia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D034181:Epimedium / Q000737:chemistry*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008819:Mice, Nude; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010936:Plant Extracts; D011799:Quinazolines; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib