title: ZD6474 inhibits proliferation and invasion of human hepatocellular carcinoma cells.
abstract: Hepatocellular carcinoma (HCC) is characterized by hypervascularization, neoangiogenesis formation and blood vessel invasion. Recently, it has been demonstrated that an inhibitor of the vascular endothelial growth factor (VEGF) receptor, ZD6474, may directly inhibit the growth of tumor cells. ZD6474 effectiveness was investigated on cell growth, apoptosis, adhesion, migration and invasion and related to the drug-dependent modulation of main molecular targets on HCC cells. ZD6474 inhibited HCC cell proliferation, however, such effect was reverted by Laminin-5 (Ln-5) but not by other extracellular matrix proteins (ECM). ZD6474 also inhibited HCC cell adhesion, migration and invasion, whereas the simultaneous treatment with the drug and Ln-5 strongly recovered those effects. Under the same experimental conditions, ZD6474 inhibited the expression of phosphorylated EGFR in all cell lines while the effect on p-Erk1/2 was dependent on cellular invasive characteristics. Nonetheless, co-incubation with Ln-5 completely recovered this effect. Our results support the hypothesis that ZD6474 could represent an interesting therapeutic opportunity for patients with HCC scarcely expressing the ECM protein, Ln-5.
authors.affiliation: Department of Internal Medicine, Immunology, and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy. g.giannelli@intmed.uniba.it
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Giannelli
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
authors.forename: Concetta
authors.initials: C
authors.lastname: Sgarra
authors.forename: Letizia
authors.initials: L
authors.lastname: Porcelli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Antonaci
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D010880:Piperidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D013997:Time Factors; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D010880:Piperidines; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; D000097794:Kalinin; C452423:vandetanib