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

Roberta Vitali, Camillo Mancini, Vincenzo Cesi, Barbara Tanno, Marta Piscitelli, Mariateresa Mancuso, Fabiola Sesti, Emanuela Pasquali, Bruno Calabretta, Carlo Dominici, Giuseppe Raschellà

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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. © 2009 UICC.
Original languageEnglish
Pages (from-to)2547 - 2555
Number of pages9
JournalInternational Journal of Cancer
Volume125
Issue number11
DOIs
Publication statusPublished - 1 Dec 2009
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

Cite this

Vitali, R., Mancini, C., Cesi, V., Tanno, B., Piscitelli, M., Mancuso, M., Sesti, F., Pasquali, E., Calabretta, B., Dominici, C., & Raschellà, G. (2009). Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model. International Journal of Cancer, 125(11), 2547 - 2555. https://doi.org/10.1002/ijc.24606