title: Marsdenia tenacissima extract enhances gefitinib efficacy in non-small cell lung cancer xenografts.
abstract: OBJECTIVE
  The stem of Marsdenia tenacissima (Roxb.) Wight et Arn. has long been used as a medicine to treat cancer in China. Our previous in vitro results showed that Marsdenia tenacissima extract (MTE) overcomes gefitinib resistance in non-small cell lung cancer (NSCLC) cells. However, it is unknown whether MTE could enhance gefitinib efficacy in vivo. The present study was intended to investigate the in vivo anti-tumour activity of MTE combined with gefitinib.
  
  
  METHODS
  Human NSCLC H460 (K-ras mutation) or H1975 cells (EGFR T790M mutation) were subcutaneously inoculated into nude mice. Tumour volume and body weight were measured regularly. Resected tumours were weighed after the animals were sacrificed. Immunoblotting or immunohistochemistry was used to assess the cellular proliferation and apoptosis in xenograft tumour tissue. Expression of the EGFR downstream pathways and c-Met were measured with western blot analysis to explore possible mechanisms.
  
  
  RESULTS
  MTE (5, 10, 20 g/kg) dose-dependently reduced tumour growth and induced cell apoptosis. MTE suppressed EGFR related signals, and 20 g/kg was the most effective dose. Low-dose MTE (5 g/kg) significantly enhanced gefitinib efficacy in resistant H460 and H1975 xenografts. The combination inhibited tumour proliferation and induced cell apoptosis in both resistant NSCLC xenografts. Constitutive activation of the PI3K/Akt and MEK/ERK pathways is related to EGFR-TKI resistance. Accordingly, phosphorylation of PI3K/Akt/mTOR and ERK1/2 was suppressed after combination treatment. Simultaneously, cross-talked c-Met and EGFR were also prominently lowered in the presence of MTE combined with gefitinib.
  
  
  CONCLUSIONS
  The present results suggest that the combination of MTE and gefitinib may be a promising therapeutic approach to enhance gefitinib efficacy in resistant NSCLC.
authors.affiliation: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China; Department of Integration of Chinese and Western Medicine, Peking University School of Oncology, Beijing 100142, PR China. Electronic address: shuyanhan@126.com.
authors.forename: Shu-Yan
authors.initials: SY
authors.lastname: Han
authors.affiliation: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China; Department of Cell Biology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China; Department of Integration of Chinese and Western Medicine, Peking University School of Oncology, Beijing 100142, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China; Department of Integration of Chinese and Western Medicine, Peking University School of Oncology, Beijing 100142, PR China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhou
authors.affiliation: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China; Department of Integration of Chinese and Western Medicine, Peking University School of Oncology, Beijing 100142, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China; Laboratory Animal Unit, Peking University Cancer Hospital & Institute, Beijing 100142, PR China.
authors.forename: Guo
authors.initials: G
authors.lastname: An
authors.affiliation: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China; Department of Integration of Chinese and Western Medicine, Peking University School of Oncology, Beijing 100142, PR China. Electronic address: lppma123@sina.com.
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D000077156:Gefitinib; D008297:Male; D031101:Marsdenia / Q000737:chemistry*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010936:Plant Extracts / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; D011799:Quinazolines; D000077156:Gefitinib
keywords: Gefitinib resistance; H1975; H460; Marsdenia tenacissima extract; NSCLC xenografts