SU5416 is a potent inhibitor of hepatocyte growth factor receptor (c-Met) and blocks HGF-induced invasiveness of human HepG2 hepatoma cells.
OBJECTIVE
SU5416 is a potent inhibitor of receptor tyrosine kinases, including those of the vascular endothelial growth factor receptor, stem cell factor receptor, and platelet-derived growth factor receptor. Because of the overwhelming evidence favoring the role of aberrant hepatocyte growth factor (HGF)/Met signaling in the pathogenesis of various human cancers, various inhibitor strategies have been employed to therapeutically target this receptor.


METHODS
Cell proliferation was determined by incorporation of [(3)H] thymidine. Invasiveness was assayed in Boyden Chambers with 8 microm Matrigel coated filters. Phosphorylation of ERK1/2, Akt by HGF stimulation was detected by Western blotting.


RESULTS
We found that SU5416 inhibited motility scattering and the invasive activity of a hepatocellular carcinoma cell line HepG2 in vitro and growth in primary cultured hepatocytes induced by HGF. Consequently, tyrosine autophosphorylation of the c-met induced by HGF was inhibited in these cells by SU5416 in a dose-dependent manner. Furthermore, ERK1/2 and Akt phosphorylation, the signaling events down-stream of c-met activation were reduced. Moreover, SU5416 caused reversion in NIH3T3 fibroblasts transformed by the oncogenic form of the receptor, Tpr-Met.


CONCLUSIONS
Inhibition of various solid tumors growth and metastasis by SU5416 may be partially attributed to blocking activation of the hepatocyte growth factor receptor.
Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, People's Republic of China.
Si Y
SY
Wang
Bing
B
Chen
Yi Q
YQ
Zhan
Wang X
WX
Xu
Chang Y
CY
Li
Ri F
RF
Yang
Hong
H
Zheng
Pei B
PB
Yue
Steven H
SH
Larsen
Hui B
HB
Sun
Xiaoming
X
Yang
D016475:3T3 Cells; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002478:Cells, Cultured; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
D007211:Indoles; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; C116890:Semaxinib; D004247:DNA; D019859:Proto-Oncogene Proteins c-met; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases