title: The dual EGF/VEGF receptor tyrosine kinase inhibitor AEE788 inhibits growth of human hepatocellular carcinoma xenografts in nude mice.
abstract: 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.
authors.affiliation: Department of Medicine 1, University Hospital Erlangen, D-91054 Erlangen, Germany.
authors.forename: Kinya
authors.initials: K
authors.lastname: Okamoto
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.forename: Beate
authors.initials: B
authors.lastname: Alinger
authors.forename: Matthias
authors.initials: M
authors.lastname: Meissnitzer
authors.forename: Gabriele
authors.initials: G
authors.lastname: Sass
authors.forename: Volker
authors.initials: V
authors.lastname: Schmitz
authors.forename: Pietro
authors.initials: P
authors.lastname: Di Fazio
authors.forename: Till
authors.initials: T
authors.lastname: Wissniowski
authors.forename: Susanne
authors.initials: S
authors.lastname: Gahr
authors.forename: Bernd
authors.initials: B
authors.lastname: Hohenstein
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kaufmann
authors.forename: Axel
authors.initials: A
authors.lastname: Schlösser
authors.forename: Ulrike
authors.initials: U
authors.lastname: Haus
authors.forename: Eckhart G
authors.initials: EG
authors.lastname: Hahn
authors.forename: Christoph
authors.initials: C
authors.lastname: Herold
authors.forename: Matthias
authors.initials: M
authors.lastname: Ocker
mesh_terms: 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*
chemical_list: D011687:Purines; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; C489254:AEE 788