title: Marsdenia tenacissima extract restored gefitinib sensitivity in resistant non-small cell lung cancer cells.
abstract: Most non-small cell lung cancer (NSCLC) patients responding to gefitinib harbor activating mutations in the epidermal growth factor receptor (EGFR). However, the responsive cases eventually develop the resistance to gefitinib. Besides, K-ras mutations were identified as the primary resistance to gefitinib. We investigated whether Marsdenia tenacissima extract (MTE, trade name: Xiao-Ai-Ping injection) combined with gefitinib could overcome the resistance of NSCLC cells to gefitinib. NSCLC cell lines with different sensitivities to gefitinib were studied. Cell growth and apoptosis were evaluated by MTT assay and flow cytometry, respectively. The EGFR-related signaling molecule phosphorylation was assessed by Western blotting. We found that MTE inhibited cell growth in gefitinib-sensitive and -resistant cells. In gefitinib-resistant cells, the MTE→MTE+gefitinib (M→M+G) treatment was most potent over the concurrent administration of MTE and gefitinib (M+G) or gefitinib→gefitinib+MTE (G→G+M) treatment in cell growth inhibition and apoptosis induction. The M→M+G treatment significantly reduced the phosphorylation of EGFR downstream signaling molecules PI3K/Akt/mTOR and ERK, on which MTE and gefitinib alone had no obvious effects on the resistant cells. The M→M+G treatment attenuated c-Met phosphorylation in H460 and H1975 as well. Thus, we found that the M→M+G treatment improved the sensitivity of resistant NSCLC cells carrying T790M or K-ras mutations to gefitinib, suggesting that the M→M+G treatment may be a promising therapeutic strategy to overcome gefitinib resistance in NSCLC.
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Integration of Chinese and Western Medicine, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing 100142, PR China.
authors.forename: Shu-Yan
authors.initials: SY
authors.lastname: Han
authors.forename: Ming-Bo
authors.initials: MB
authors.lastname: Zhao
authors.forename: Gui-Bao
authors.initials: GB
authors.lastname: Zhuang
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D031101:Marsdenia / Q000737:chemistry*; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C121623:PSMF1 protein, human; D010936:Plant Extracts; D011506:Proteins; D011799:Quinazolines; C546842:MTOR protein, human; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex; D000077156:Gefitinib