title: Antiproliferative and proapoptotic activities of new pyrazolo[3,4-d]pyrimidine derivative Src kinase inhibitors in human osteosarcoma cells.
abstract: 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.
authors.affiliation: Università degli Studi di Siena, Dipartimento di Biologia Molecolare, via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Spreafico
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Tommaso
authors.initials: T
authors.lastname: Serchi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Orlandini
authors.forename: Adriano
authors.initials: A
authors.lastname: Angelucci
authors.forename: David
authors.initials: D
authors.lastname: Magrini
authors.forename: Giulia
authors.initials: G
authors.lastname: Bernardini
authors.forename: Giulia
authors.initials: G
authors.lastname: Collodel
authors.forename: Anna
authors.initials: A
authors.lastname: Di Stefano
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.forename: Mauro
authors.initials: M
authors.lastname: Bologna
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Annalisa
authors.initials: A
authors.lastname: Santucci
mesh_terms: 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*
chemical_list: C412373:AG 1879; D011720:Pyrazoles; D011743:Pyrimidines; C529160:SI-83 compound; D019061:src-Family Kinases