Antiproliferative and proapoptotic activities of new pyrazolo[3,4-d]pyrimidine derivative Src kinase inhibitors in human osteosarcoma cells.

Osteosarcoma is the most frequent primitive malignant tumor of the skeletal system, characterized by an extremely aggressive clin. course that still lacks an effective treatment. Src kinase seems to be involved in the osteosarcoma malignant phenotype. The authors show that the treatment of human osteosarcoma cell lines with a new pyrazolo[3,4-d]pyrimidine deriv. Src inhibitor, namely SI-83, impaired cell viability, with a half-maximal inhibitory concn. of 12 μM in nonstarved cells and a kinetic different from that known for the Src inhibitor PP2. Anal. 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 compd. with low toxicity for nonneoplastic cells