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Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model.

TitoloActivity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model.
Tipo di pubblicazioneArticolo su Rivista peer-reviewed
Anno di Pubblicazione2009
AutoriVitali, Roberta, Mancini Camillo, Cesi Vincenzo, Tanno Barbara, Piscitelli Marta, Mancuso Mariateresa, Sesti Fabiola, Pasquali Emanuela, Calabretta Bruno, Dominici Carlo, and Raschellà Giuseppe
RivistaInt J Cancer
Volume125
Issue11
Paginazione2547-55
Data di pubblicazione2009 Dec 01
ISSN10970215
Parole chiaveAnimals, Apoptosis, Cell Aging, Cell Line, Tumor, cell proliferation, dasatinib, Disease Models, Animal, Female, Flow cytometry, Humans, Immunoenzyme Techniques, In Vitro Techniques, Mice, Mice, Nude, Neoplasm Invasiveness, Neuroblastoma, Phosphorylation, Protein Kinase Inhibitors, Pyrimidines, Thiazoles, Xenograft Model Antitumor Assays
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.

Note

cited By 26

URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-70350721795&doi=10.1002%2fijc.24606&partnerID=40&md5=f116a2642bfa41d23e3e4a4627086a68
DOI10.1002/ijc.24606
Alternate JournalInt. J. Cancer
Citation Key5070
PubMed ID19623650
Grant ListR01 CA95111 / CA / NCI NIH HHS / United States