Premium
Antiproliferative and proapoptotic activities of new pyrazolo[3,4‐ d ]pyrimidine derivative Src kinase inhibitors in human osteosarcoma cells
Author(s) -
Spreafico Adriano,
Sche 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
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-9873com
Subject(s) - osteosarcoma , proto oncogene tyrosine protein kinase src , cancer research , apoptosis , chemistry , kinase , biology , biochemistry
Osteosarcoma is the most frequent primitive malignant tumor of the skeletal system, char acterized 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 μ.M 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 com pound 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 proapo‐ ptotic activities of new pyrazolo[3,4‐d]pyrimidine deriv ative Src kinase inhibitors in human osteosarcoma cells. FASEBJ. 22, 1560–1571 (2008)