title: Sorafenib inhibits 5-fluorouracil-resistant gastric cancer cell growth.
abstract: BACKGROUND
  Sorafenib is a multi-kinase inhibitor used in the treatment of various cancers. This study investigated the inhibitory effect of sorafenib on xenograft models of gastric cancer cells and 5-fluorouracil (5-FU)-resistant cells.
  
  
  METHODS
  The half-maximal inhibitory concentration (IC50) of sorafenib in NCI-N87 cells was determined. Xenograft models were established using BALB/c nude mice and were divided into four groups treated with vehicle, sorafenib (20 mg kg-1day-1), 5-FU (50 mg kg-1week-1), or a combination of sorafenib (20 mg kg-1day-1) plus 5-FU (50 mg kg-1week-1). 5-FU-resistant NCI-N87 cells were established by repeated exposure to 5-FU.
  
  
  RESULTS
  Sorafenib inhibited NCI-N87 cell growth in a concentration-dependent manner with a mean IC50of 16.345 ± 5.391 μM. Phosphorylation levels of mitogen-activated protein kinase kinase and extracellular signal-regulated kinase in these cells decreased in a dose-dependent manner after exposure to sorafenib. Sorafenib induced the activation of caspase-3, and its combination with 5-FU more effectively inhibited the growth of xenograft tumors than either sorafenib or 5-FU alone (p < 0.05). Sorafenib markedly inhibited 5-FU-resistant NCI-N87 cell growth as well as sphere formation in both parental and 5-FU-resistant NCI-N87 cells.
  
  
  CONCLUSIONS
  The sorafenib and 5-FU combination exhibited enhanced antitumor effects in a gastric cancer xenograft model and inhibited 5-FU-resistant cell proliferation and sphere formation. These findings suggest that sorafenib is useful in overcoming gastric cancer resistance to conventional chemotherapy.
authors.affiliation: a Division of Gastroenterology, Department of Internal Medicine and Yonsei Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Republic of Korea.|b Division of Gastroenterology and Hepatology, Department of Internal Medicine , Yonsei University Wonju College of Medicine , Wonju , Republic of Korea.
authors.forename: Hee Man
authors.initials: HM
authors.lastname: Kim
authors.affiliation: a Division of Gastroenterology, Department of Internal Medicine and Yonsei Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Republic of Korea.
authors.forename: Sun A
authors.initials: SA
authors.lastname: Kim
authors.affiliation: a Division of Gastroenterology, Department of Internal Medicine and Yonsei Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Republic of Korea.
authors.forename: Soo Been
authors.initials: SB
authors.lastname: Park
authors.affiliation: a Division of Gastroenterology, Department of Internal Medicine and Yonsei Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Republic of Korea.|c Division of Gastroenterology, Department of Internal Medicine , Gachon University Gil Medical Center , Incheon , Republic of Korea.
authors.forename: Jae Hee
authors.initials: JH
authors.lastname: Cho
authors.affiliation: a Division of Gastroenterology, Department of Internal Medicine and Yonsei Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Republic of Korea.|d Brain Korea 21 Project for Medical Science , Yonsei University College of Medicine , Seoul , Republic of Korea.
authors.forename: Si Young
authors.initials: SY
authors.lastname: Song
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D000077157:Sorafenib; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D005472:Fluorouracil
keywords: 5-fluorouracil; Gastric cancer; drug resistance; neoplastic stem cell; sorafenib; sphere formation