title: Potent in vitro and in vivo antitumor activity of sorafenib against human intrahepatic cholangiocarcinoma cells.
abstract: BACKGROUND
  Intrahepatic cholangiocarcinoma (ICC) is rising in clinical importance due to the increasing incidence worldwide, poor prognosis, and suboptimal response to therapies. New effective therapeutic approaches are needed for improvement of treatment outcome. A recent study showed that sorafenib, a multikinase inhibitor that acts predominantly through inhibition of Raf kinase and vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, exhibited potent antitumor activity in a preclinical model of cholangiocarcinoma cells.
  
  
  METHODS
  We tested the in vitro and in vivo antitumor activity of sorafenib against human ICC cell lines.
  
  
  RESULTS
  Treatment of ICC cells with sorafenib resulted in inhibition of proliferation and induction of apoptosis in the cell lines. In the cells treated with sorafenib, phosphorylation of mitogen-activated protein kinase kinase (MEK) and mitogen-activated protein kinase (MAPK) and also interleukin-6-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) were inhibited in a dose-dependent manner. Down-regulation of the anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) paralleled the reduced phosphorylation of STAT3. However, sorafenib induced no significant change in the cell cycle distribution and the expression levels of cyclin D1 and p27(Kip1) in the cells. For the in vivo antitumor activity, oral administration of sorafenib significantly inhibited the growth of subcutaneous tumors established in immunodeficient mice at doses of 10, 30, and 100 mg/kg. Moreover, administration of sorafenib (30 mg/kg) to animals with peritoneally disseminated ICC resulted in significantly prolonged survival compared with that of untreated animals (76 vs. 43 days in treated and vehicle-treated mice, respectively).
  
  
  CONCLUSIONS
  These results indicate that sorafenib is a potent agent that may provide a new therapeutic option for human ICC.
authors.affiliation: Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Onuki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ishige
authors.forename: Nobue
authors.initials: N
authors.lastname: Baba
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ueda
authors.forename: Sachiko
authors.initials: S
authors.lastname: Matsuda
authors.forename: Kaoru
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Onodera
authors.forename: Yasuni
authors.initials: Y
authors.lastname: Nakanuma
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamato
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Ichinosuke
authors.initials: I
authors.lastname: Hyodo
authors.forename: Junichi
authors.initials: J
authors.lastname: Shoda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000494:pharmacology*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D000077157:Sorafenib; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib