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 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 microM 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
Adriano
A
Università degli Studi di Siena, Dipartimento di Biologia Molecolare, via Fiorentina 1, 53100 Siena, Italy.
Schenone
Silvia
S
Serchi
Tommaso
T
Orlandini
Maurizio
M
Angelucci
Adriano
A
Magrini
David
D
Bernardini
Giulia
G
Collodel
Giulia
G
Di Stefano
Anna
A
Tintori
Cristina
C
Bologna
Mauro
M
Manetti
Fabrizio
F
Botta
Maurizio
M
Santucci
Annalisa
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010006:Osteoblasts / Q000187:drug effects; D012516:Osteosarcoma / Q000188:drug therapy*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C412373:AG 1879; D011720:Pyrazoles; D011743:Pyrimidines; C529160:SI-83 compound; D019061:src-Family Kinases