Abstract
Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma), a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the 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 a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma) and POS-1 (undifferentiated osteosarcoma). Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R), appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor status of patients.
Highlights
Osteosarcoma is a rare bone tumour mainly affecting young patients, defined by the presence of tumour cells producing an osteoid matrix [1]
Imatinib mesylate decreased the number of viable osteosarcoma cells in a dose-dependent manner [IC50 at 72 hours: 20 mM (MG-63), 11 mM (HOS), 23 mM (MOS-J), 15 mM (POS-1); 9 mM (OSRGA); IC90 at 72 h: 30 mM (MG-63), 19 mM (HOS), 28 mM (MOS-J), 24 mM (POS-1); 16 mM (OSRGA)] with a maximum effect at 30 mM for most of the cells assessed (Figure 1D)
To determine whether the effects of imatinib mesylate on osteosarcoma cells resulted from the inhibition of cell proliferation and/or the induction of cell death, the number of cell divisions determined by time-lapse microscopy was manually counted
Summary
Osteosarcoma is a rare bone tumour mainly affecting young patients (peak of incidence around 18 years old), defined by the presence of tumour cells producing an osteoid matrix [1]. The current therapeutic sequence for high-grade osteosarcoma was proposed by Rosen et al in the 1970s and is internationally accepted [2]. This treatment is based on neo-adjuvant chemotherapy, delayed en-bloc wide resection, and adjuvant chemotherapy adapted to the histologic profile assessed on tumour tissue removed during surgery. In the last 10 years, better knowledge of oncogenic processes in osteosarcoma has led to the development of new therapeutic approaches based on single new drugs or administered in combination with conventional chemotherapy [4]. The combination of apomine and lovastatine which targets the mevalonate pathways significantly reduced tumour progression in osteosarcoma-bearing mice compared to single treatment which had no effect at the doses used [5].
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