title: Combined therapeutic effect and molecular mechanisms of metformin and cisplatin in human lung cancer xenografts in nude mice.
abstract: OBJECTIVE
  This work was aimed at studying the inhibitory activity of metformin combined with the commonly used chemotherapy drug cisplatin in human lung cancer xenografts in nude mice. We also examined the combined effects of these drugs on the molecular expression of survivin, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor-C (VEGF-C), and vascular endothelial growth factor receptor-3 (VEGFR-3) to determine the mechanism of action and to explore the potential applications of the new effective drug therapy in lung cancer.
  
  
  METHODS
  The nude mice model of lung cancer xenografts was established, and mice were randomly divided into the metformin group, the cisplatin group, the metformin + cisplatin group, and the control group. The animals were killed 42 days after drug administration, and the tumor tissues were then sampled to detect the messenger ribonucleic acid (mRNA) and protein expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR).
  
  
  RESULTS
  The protein and mRNA expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 in the cisplatin group and the combined treatment group were lower than that in the control group (P < 0.05). In the metformin group, the expression of MMP-2 protein and mRNA was lower than that in the control group (P < 0.05). The protein and mRNA expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 in the combined treatment group were lower than that in the cisplatin group and the metformin group (P < 0.05).
  
  
  CONCLUSIONS
  Metformin inhibited the expression of MMP-2, cisplatin and the combined treatment inhibited the expression of survivin, MMP-2, VEGF-C, and VEGFR-3, and the combined treatment of metformin with cisplatin resulted in enhanced anti-tumor efficacy.
authors.forename: Yu-Qin
authors.initials: YQ
authors.lastname: Chen
authors.affiliation: Department of Respiratory Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D012097:Repressor Proteins; D000077022:Survivin; D042582:Vascular Endothelial Growth Factor C; D008687:Metformin; D040321:Vascular Endothelial Growth Factor Receptor-3; D020778:Matrix Metalloproteinase 2; D002945:Cisplatin