title: In vitro antiproliferative and antimigratory activity of dasatinib in neuroblastoma and Ewing sarcoma cell lines.
abstract: Neuroblastoma (NB) and Ewing sarcoma (ES) are neuroectodermal tumors typical of pediatric age that, despite aggressive treatment, still present a poor prognosis when in advanced stages. Studies indicate that c-KIT and platelet-derived growth factor receptor (PDGFR) play a substantial role in the proliferation and survival of NB and ES cells. Dasatinib, an oral multi-targeted inhibitor of several kinases including BCR-ABL and SRC-family kinases, is also active against c-KIT and PDGFR. Here, we evaluated the effect of dasatinib on the NB cell lines SJ-N-KP, SK-N-BE, AF8 and IMR5, and on the ES lines PDE02, TC106 and 6647. Proliferation and viability assays showed that dasatinib exerts an antiproliferative activity with a peak effect occurring at 24 h. After a 24-h exposure to dasatinib at 100 nM, proliferation was inhibited by 29.4+/-5.7% in SJ-N-KP, 41.3+/-11.7% in IMR5, 35.3+/-7.6% in PDE02 and 14+/-10.6% in 6647. Dasatinib did not induce apoptosis in NB and ES cell lines. A possible antimigratory activity of dasatinib was evaluated by scratch test. Dasatinib at 100 nM inhibited the migration of NB and ES cell lines by a mean of 30.2 and 25.3%, respectively. This activity suggests a possible role of dasatinib in inhibiting metastasis and appears of particular interest, given the association between metastatic disease and poor prognosis in these tumors. In conclusion, the cytostatic and antimigratory activity of dasatinib in NB and ES cell lines and the lack of pro-apoptotic activity suggests a possible use for this compound in the treatment of these tumors as a combination with other cytotoxic therapy.
authors.affiliation: Pediatric Hematology Unit, University of Torino, Piazza Polonia 94, Turin, Italy. fabio.timeus@unito.it
authors.forename: Fabio
authors.initials: F
authors.lastname: Timeus
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Crescenzio
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Fandi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Doria
authors.forename: Luiselda
authors.initials: L
authors.lastname: Foglia
authors.forename: Luca
authors.initials: L
authors.lastname: Cordero di Montezemolo
mesh_terms: D001859:Bone Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D000069439:Dasatinib; D006801:Humans; D009447:Neuroblastoma / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012512:Sarcoma, Ewing / Q000473:pathology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib