SRC family kinase (SFK) inhibition reduces rhabdomyosarcoma cell growth in vitro and in vivo and triggers p38 MAP kinase-mediated differentiation
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Nadia Casini1, Iris Maria Forte2, Gianmarco Mastrogiovanni1, Francesca Pentimalli2, Adriano Angelucci3, Claudio Festuccia3, Valentina Tomei1, Elisa Ceccherini1, Domenico Di Marzo2, Silvia Schenone4, Maurizio Botta5,6, Antonio Giordano1,2,6, Paola Indovina1,6
1Department of Medicine, Surgery and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, Italy
2Oncology Research Center of Mercogliano (CROM), Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale”, IRCCS, Naples, Italy
3Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
4Pharmacy Department, University of Genoa, Genoa, Italy
5Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
6Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia PA, USA
Antonio Giordano, e-mail: email@example.com
Paola Indovina, e-mail: firstname.lastname@example.org
Keywords: rhabdomyosarcoma, SRC family inhibition, NOTCH3, muscle differentiation, p38 MAPK, YES
Received: August 01, 2014 Accepted: January 07, 2015 Published: February 03, 2015
Recent data suggest that SRC family kinases (SFKs) could represent potential therapeutic targets for rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children. Here, we assessed the effect of a recently developed selective SFK inhibitor (a pyrazolo[3,4-d]pyrimidine derivative, called SI221) on RMS cell lines. SI221, which showed to be mainly effective against the SFK member YES, significantly reduced cell viability and induced apoptosis, without affecting non-tumor cells, such as primary human skin fibroblasts and differentiated C2C12 cells. Moreover, SI221 decreased in vitro cell migration and invasion and reduced tumor growth in a RMS xenograft model. SFK inhibition also induced muscle differentiation in RMS cells by affecting the NOTCH3 receptor-p38 mitogen-activated protein kinase (MAPK) axis, which regulates the balance between proliferation and differentiation. Overall, our findings suggest that SFK inhibition, besides reducing RMS cell growth and invasive potential, could also represent a differentiation therapeutic strategy for RMS.
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