Bone Abstracts

Osteosarcoma is the most common primary malignant bone tumor, characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments points out the importance of exploring new therapeutic ways. Imatinib Mesylate (Glivec, Novartis Pharma), a tyrosine kinase inhibitor, has been originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that Imatinib Mesylate inhibits osteoclast differentiation through M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two tyrosine kinase receptors. The present study investigated the in vitro effects of Imatinib Mesylate on proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1). Imatinib Mesylate was also assessed as curative and preventive treatments in two syngenic osteosarcoma models: MOS-J (osteoblastic osteosarcoma) and POS-1 (osteolytic osteosarcomal). Imatinib Mesylate has a dose-dependent anti-proliferative effect in all cell lines studied. The drug induces a G0/G1 cell cycle arrest in all cell lines, excepted for MOS-J cells which are blocked in S/G2M phases. Furthermore, Imatinib Mesylate induces a caspase-dependent apoptosis and strongly inhibits osteosarcoma cell migration. Western-blot experiments revealed that Imatinib Mesylate inhibits Akt/mTOR pathways and interestingly induces ERK1/2 phosphorylation that may partly explain the limited therapeutic answer in patients. In MOS-J osteosarcoma model, Imatinib Mesylate oral administration (50–100 mg/kg per day) significantly inhibits the tumor development (60–70%), and exerts its activity in preventive and curative approaches. Micro-CT analysis did not show any effects on the tumor-associated osteolysis. These results suggest that Imatinib Mesylate may represent a promising therapeutic candidate for osteosarcoma according to the MAPK-kinase status of patients.