title: SRC Family Kinase Inhibition in Ewing Sarcoma Cells Induces p38 MAP Kinase-Mediated Cytotoxicity and Reduces Cell Migration.
abstract: Ewing sarcoma (ES) is a highly aggressive bone and soft tissue cancer, representing the second most common primary malignant bone tumor in children and adolescents. Although the development of a multimodal therapy, including both local control (surgery and/or radiation) and systemic multidrug chemotherapy, has determined a significant improvement in survival, patients with metastatic and recurrent disease still face a poor prognosis. Moreover, considering that ES primarily affects young patients, there are concerns about long-term adverse effects of the therapy. Therefore, more rational strategies, targeting specific molecular alterations underlying ES, are required. Recent studies suggest that SRC family kinases (SFKs), which are aberrantly activated in most cancer types, could represent key therapeutic targets also for ES. Here, we challenged ES cell lines with a recently developed selective SFK inhibitor (a pyrazolo[3,4-d]pyrimidine derivative, called SI221), which was previously shown to be a valuable proapoptotic agent in other tumor types while not affecting normal cells. We observed that SI221 significantly reduced ES cell viability and proved to be more effective than the well-known SFK inhibitor PP2. SI221 was able to induce apoptosis in ES cells and also reduced ES cell clonogenic potential. Furthermore, SI221 was also able to reduce ES cell migration. At the molecular level, our data suggest that SFK inhibition through SI221 could reduce ES cell viability at least in part by hindering an SFK-NOTCH1 receptor-p38 mitogen-activated protein kinase (MAPK) axis. Overall, our study suggests a potential application of specific SFK inhibition in ES therapy. J. Cell. Physiol. 232: 129-135, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, Italy. pindovina@inwind.it.|Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania. pindovina@inwind.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Indovina
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 Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Iris Maria
authors.initials: IM
authors.lastname: Forte
authors.affiliation: AORN Dei Colli Monaldi UOC, Oncology, Naples, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Garofano
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cesari
authors.affiliation: Oncology Research Center of Mercogliano (CROM), Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Carmelina Antonella
authors.initials: CA
authors.lastname: Iannuzzi
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Del Porro
authors.affiliation: Oncology Research Center of Mercogliano (CROM), Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pentimalli
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Napoliello
authors.affiliation: Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania.
authors.forename: Silvia
authors.initials: S
authors.lastname: Boffo
authors.affiliation: Pharmacy Department, University of Genoa, Genoa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.affiliation: Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania.|Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.affiliation: Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania. giordano@temple.edu.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D012512:Sarcoma, Ewing / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C000618489:SI221 compound; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases