Antiproliferative and proapoptotic activities of new pyrazolo3,4- d pyrimidine derivative Src kinase inhibitors in human osteosarcoma cells Adriano Spreafico † , Silvia Schenone || , Tommaso Serchi * , Maurizio Orlandini * , Adriano Angelucci ¶ , David Magrini * , Giulia Bernardini * , Giulia Collodel § , Anna Di Stefano * , Cristina Tintori ‡ , Mauro Bologna ¶ , Fabrizio Manetti ‡ , Maurizio Botta ‡ ,1 and Annalisa Santucci * ,1 * Dipartimento di Biologia Molecolare; † Dipartimento di Medicina Clinica e Scienze Immunologiche, Policlinico Le Scotte; ‡ Dipartimento Farmaco Chimico Tecnologico; § Dipartimento di Chirurgia, Sezione di Biologia Applicata, Policlinico Le Scotte, Università degli Studi di Siena, Siena, Italy; || Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Genova, Italy; and ¶ Dipartimento di Biologia di Base ed Applicata, Università degli Studi dell’Aquila, Coppito L’Aquila, Italy 1 Correspondence: A.S., Università degli Studi di Siena, Dipartimento di Biologia Molecolare, via Fiorentina 1, 53100 Siena, Italy. E-mail: santucci@unisi.it ; M.B., Università degli Studi di Siena, Dipartimento Farmaco Chimico Tecnologico, via A. Moro, 53100 Siena, Italy. E-mail: botta@unisi.it Osteosarcoma is the most frequent primitive malignant tumor of the skeletal system, characterized by an extremely aggressive clinical course that still lacks an effective treatment. Src kinase seems to be involved in the osteosarcoma malignant phenotype. We show that the treatment of human osteosarcoma cell lines with a new pyrazolo3,4- d pyrimidine derivative Src inhibitor, namely SI-83, impaired cell viability, with a half-maximal inhibitory concentration of 12 µM in nonstarved cells and a kinetic different from that known for the Src inhibitor PP2. Analysis by terminal deoxynucleotidyl transferase-mediated nick end labeling, Hoechst, and flow cytometric assay showed that SI-83 induced apoptosis in SaOS-2 cells. Moreover, SI-83, by inhibiting Src phosphorylation, decreased in vivo osteosarcoma tumor mass in a mouse model. Finally, SI-83 showed selectivity for osteosarcoma, since it had a far lower effect in primary human osteoblasts. These results show that human osteosarcoma had Src-dependent proliferation and that modulation of Src activity may be a therapeutic target of this new compound with low toxicity for nonneoplastic cells —Spreafico, A., Schenone, S., Serchi, T., Orlandini, M., Angelucci, A., Magrini, D., Bernardini, G., Collodel, G., Di Stefano, A., Tintori, C., Bologna, M., Manetti, F., Botta, M., Santucci, A. Antiproliferative and proapoptotic activities of new pyrazolo3,4- d pyrimidine derivative Src kinase inhibitors in human osteosarcoma cells. Key Words: bone cells • apoptosis • bone cancer • osteoblast • tyrosine kinase
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Antiproliferative and proapoptotic activities of new pyrazolo3,4-dpyrimidine derivative Src kinase inhibitors in human osteosarcoma cells
Spreafico, Adriano; Schenone, Silvia; Serchi, Tommaso; Orlandini, Maurizio; Angelucci, Adriano; Magrini, David; Bernardini, Giulia; Collodel, Giulia; Di Stefano, Anna; Tintori, Cristina; Bologna, Mauro; Manetti, Fabrizio; Botta, Maurizio; Santucci, Annalisa
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, Volume 22 (5): 1560
Fed of American Socs for Experimental Biology – May 1, 2008
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