title: Synergistic antitumor effects of dasatinib and oxaliplatin in gastric cancer cells.
abstract: OBJECTIVE
  The aim of this study is to investigate whether dasatinib, a Src inhibitor, has the synergistic effect with oxaliplatin in treating gastric cancer cells.
  
  
  METHODS
  The baseline levels of total Src and p-Src in 10 human gastric cancer cell lines and gastric mucosa epithelial cell line GES-1 were detected by Western blot (WB). The changes of Src and p-Src expression after oxaliplatin exposure were evaluated by WB. The combination indices and clonogenic assay were used to evaluate the synergistic effects of dasatinib with oxaliplatin on cell growth and proliferation in vitro. Gastric cancer xenografts in nude mice were established and treated by oxaliplatin with or without dasatinib. The tumor growth curves were calculated and the impacts of different treatment on the tumor proliferation and src protein expression in gastric cancer xenografts were determined by immunohistochemistry staining and WB.
  
  
  RESULTS
  The different levels of Src expression in gastric cancer cells were related with their different sensitivity to oxaliplatin. The expression of p-Src, but not total Src, was elevated after oxaliplatin exposure both in vitro and in vivo. Dasatinib could dramatically inhibit p-Src expression, and combination indices demonstrated that dasatinib and oxaliplatin were synergistic in inhibiting gastric cancer cell growth. Dasatinib plus oxaliplatin were more effective in inhibiting clone formation than oxaliplatin or dasatinib monotherapy in clonogenic assay. The tumor volume and tumor weight of xenografts were significantly lower in doublet treatment group than those in single-agent treatment groups.
  
  
  CONCLUSIONS
  Dasatinib plays synergistic role with oxaliplatin in inhibiting gastric cancer cell growth both in vitro and in vivo, via inhibiting Src activity stimulated by oxaliplatin.
authors.affiliation: Department of Surgery, Shanghai Institute of Digestive Surgery, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.forename: Bingxiang
authors.initials: B
authors.lastname: Lou
authors.forename: Jun
authors.initials: J
authors.lastname: Ji
authors.forename: Hailong
authors.initials: H
authors.lastname: Shi
authors.forename: Chenfei
authors.initials: C
authors.lastname: Zhou
authors.forename: Yingyan
authors.initials: Y
authors.lastname: Yu
authors.forename: Bingya
authors.initials: B
authors.lastname: Liu
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Zhu
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D045744:Cell Line, Tumor; D000069439:Dasatinib; D004357:Drug Synergism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000077150:Oxaliplatin; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D034622:RNA Interference; D011897:Random Allocation; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000077150:Oxaliplatin; D016392:Proto-Oncogene Proteins pp60(c-src); D000069439:Dasatinib