title: Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model.
abstract: Stage 4 neuroblastoma (NB) is a devastating childhood cancer whose poor outcome has remained essentially unchanged in the last 20 years. Receptor tyrosine kinases have important roles in the control of proliferation, differentiation and apoptosis of NB cells. Thus, we tested the activity of second-generation tyrosine kinase inhibitor Dasatinib in human NB cell lines in vitro and in an orthotopic mouse model. Dasatinib inhibited cell viability with an IC(50) in the submicromolar range in 7 of 10 tested cell lines. In sensitive cells, Dasatinib reduced anchorage-independent growth and, in some instances, induced senescence and apoptosis. In HTLA-230 cells, Dasatinib treatment caused down-regulation of c-Kit and c-Src phosphorylation in conjunction with strong inhibition of Erk1/2 and Akt activity. To test the efficacy of Dasatinib in vivo, HTLA-230 and SY5Y cells were orthotopically injected in the adrenal gland of nude mice and drug treatments carried out until day 40. In mice injected with HTLA-230 cells, tumour growth was significantly inhibited at the dose of 30 mg/(kg day) when treatment was started 7 days after injection. In animals injected with SY5Y cells that were exquisitely sensitive in vitro (IC(50)= 92 nM), the antitumour effect of Dasatinib was observed at the dose of 60 mg/(kg day) but only when treatment was started 1 day after injection. However, the anti-tumour effect of Dasatinib in vivo was partial in both orthotopic models, emphasizing the importance of testing candidate new drugs in animal environments closely mimicking the human tumour.
authors.affiliation: Section of Toxicology and Biomedical Sciences, Research Center Casaccia, ENEA, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Vitali
authors.forename: Camillo
authors.initials: C
authors.lastname: Mancini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cesi
authors.forename: Barbara
authors.initials: B
authors.lastname: Tanno
authors.forename: Marta
authors.initials: M
authors.lastname: Piscitelli
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Mancuso
authors.forename: Fabiola
authors.initials: F
authors.lastname: Sesti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pasquali
authors.forename: Bruno
authors.initials: B
authors.lastname: Calabretta
authors.forename: Carlo
authors.initials: C
authors.lastname: Dominici
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Raschellà
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D000069439:Dasatinib; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib