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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: fj.07-9873comv1 fj.07-9873comv2 22/5/1560    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Spreafico, A. Articles by Santucci, A. PubMed PubMed Citation Articles by Spreafico, A. Articles by Santucci, A.

Antiproliferative and proapoptotic activities of new pyrazolo[3,4-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

¹Correspondence: A.S., Università degli Studi di Siena, Dipartimento di Biologia Molecolare, via Fiorentina 1, 53100 Siena, Italy. E-mail: santucci{at}unisi.it; M.B., Università degli Studi di Siena, Dipartimento Farmaco Chimico Tecnologico, via A. Moro, 53100 Siena, Italy. E-mail: botta{at}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 pyrazolo[3,4-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 pyrazolo[3,4-d]pyrimidine derivative Src kinase inhibitors in human osteosarcoma cells.

Key Words: bone cells • apoptosis • bone cancer • osteoblast • tyrosine kinase