The dual EGF/VEGF receptor tyrosine kinase inhibitor AEE788 inhibits growth of human hepatocellular carcinoma xenografts in nude mice.
We investigated the effect of AEE788, a novel dual receptor tyrosine kinase inhibitor of the EGF and the VEGF receptor, for treatment of human HCC cell lines and in a subcutaneous xenograft model. Cell viability and apoptosis of HepG2 and Hep3B cells incubated with 0.1-100 microM AEE788 were quantified. In vivo, HepG2 cells were xenografted to NMRI mice and animals were treated orally with 50 mg/kg AEE788 3x/week. Immunohistochemistry and quantitative Western blotting was performed for pathway analysis in vitro and in vivo. AEE788 reduced growth and induced apoptosis of HCC cells by disrupting mitochondrial transmembrane potentials and inhibiting MAPK phosphorylation. In the xenografts, AEE788 lead to a reduced tumor growth by reducing proliferation and vascularisation. Except for a reversible skin reaction and weight loss, no signs of toxicity were observed. AEE788 is a promising new option for the treatment of HCC.
Okamoto
Kinya
K
Department of Medicine 1, University Hospital Erlangen, D-91054 Erlangen, Germany.
Neureiter
Daniel
D
Alinger
Beate
B
Meissnitzer
Matthias
M
Sass
Gabriele
G
Schmitz
Volker
V
Di Fazio
Pietro
P
Wissniowski
Till
T
Gahr
Susanne
S
Hohenstein
Bernd
B
Kaufmann
Bernhard
B
Schlösser
Axel
A
Haus
Ulrike
U
Hahn
Eckhart G
EG
Herold
Christoph
C
Ocker
Matthias
M
D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects; D009368:Neoplasm Transplantation; D011687:Purines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*
D011687:Purines; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; C489254:AEE 788