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Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model
Author(s) -
Vitali Roberta,
Mancini Camillo,
Cesi Vincenzo,
Tanno Barbara,
Piscitelli Marta,
Mancuso Mariateresa,
Sesti Fabiola,
Pasquali Emanuela,
Calabretta Bruno,
Dominici Carlo,
Raschellà Giuseppe
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24606
Subject(s) - dasatinib , tyrosine kinase inhibitor , apoptosis , tyrosine kinase , in vivo , neuroblastoma , cancer research , medicine , proto oncogene tyrosine protein kinase src , in vitro , pharmacology , cell culture , biology , cancer , receptor , biochemistry , genetics , microbiology and biotechnology
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. © 2009 UICC