title: Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.
abstract: BACKGROUND
  Dovitinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptor β. Dovitinib is currently in clinical trials for the treatment of hepatocellular carcinoma (HCC).
  
  
  METHODS
  In this study, we used five HCC cell lines and five endothelial cell lines to validate molecular and cellular targets of dovitinib.
  
  
  RESULTS
  Tumor growth and pulmonary metastasis were significantly suppressed in an orthotopic HCC model. Immunoblotting revealed that among known dovitinib targets, only PDGFR-β was expressed in two HCC cell lines, while four of five endothelial lines expressed PDGFR-β, FGFR-1, and VEGFR-2. Dovitinib inhibited endothelial cell proliferation and motility at 0.04 μmol/L, a pharmacologically relevant concentration; it was unable to inhibit the proliferation or motility of HCC cells at the same concentration. Immunohistochemical analyses showed that dovitinib significantly decreased the microvessel density of xenograft tumors, inhibiting proliferation and inducing apoptosis in HCC cells.
  
  
  CONCLUSIONS
  Our findings indicate that dovitinib inhibits HCC growth and metastasis preferentially through an antiangiogenic mechanism, not through direct targeting of HCC cells.
authors.affiliation: Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, China.
authors.forename: Zhi-Yuan
authors.initials: ZY
authors.lastname: Chen
authors.forename: Ming
authors.initials: M
authors.lastname: Shi
authors.forename: Li-Xia
authors.initials: LX
authors.lastname: Peng
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Xin-Jian
authors.initials: XJ
authors.lastname: Li
authors.forename: Zhi-Xing
authors.initials: ZX
authors.lastname: Guo
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.forename: Chong
authors.initials: C
authors.lastname: Zhong
authors.forename: Chao-Nan
authors.initials: CN
authors.lastname: Qian
authors.forename: Rong-Ping
authors.initials: RP
authors.lastname: Guo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D020794:Receptor Protein-Tyrosine Kinases