title: SRC family kinase (SFK) inhibition reduces rhabdomyosarcoma cell growth in vitro and in vivo and triggers p38 MAP kinase-mediated differentiation.
abstract: 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.
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Casini
authors.affiliation: Oncology Research Center of Mercogliano (CROM), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy.
authors.forename: Iris Maria
authors.initials: IM
authors.lastname: Forte
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, Italy.
authors.forename: Gianmarco
authors.initials: G
authors.lastname: Mastrogiovanni
authors.affiliation: Oncology Research Center of Mercogliano (CROM), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pentimalli
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Angelucci
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Festuccia
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Tomei
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Ceccherini
authors.affiliation: Oncology Research Center of Mercogliano (CROM), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Di Marzo
authors.affiliation: Pharmacy Department, University of Genoa, Genoa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia PA, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, Italy.|Oncology Research Center of Mercogliano (CROM), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia PA, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia PA, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Indovina
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D016133:Polymerase Chain Reaction; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012208:Rhabdomyosarcoma / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D011743:Pyrimidines; C014175:pyrazolo(3,4-d)pyrimidine; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: NOTCH3; SRC family inhibition; YES; muscle differentiation; p38 MAPK; rhabdomyosarcoma