title: Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models.
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.
authors.affiliation: INSERM, UMR 957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France.
authors.forename: Bérengère
authors.initials: B
authors.lastname: Gobin
authors.affiliation: INSERM, UMR 957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France.
authors.forename: Gatien
authors.initials: G
authors.lastname: Moriceau
authors.affiliation: INSERM, UMR 957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; Equipe LIGUE Nationale Contre le Cancer 2012, Nantes, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ory
authors.affiliation: INSERM, UMR 957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; Equipe LIGUE Nationale Contre le Cancer 2012, Nantes, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Charrier
authors.affiliation: INSERM, UMR 957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; Equipe LIGUE Nationale Contre le Cancer 2012, Nantes, France; CHU de Nantes, Nantes, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Brion
authors.affiliation: INSERM, UMR 957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; Equipe LIGUE Nationale Contre le Cancer 2012, Nantes, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Blanchard
authors.affiliation: INSERM, UMR 957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; Equipe LIGUE Nationale Contre le Cancer 2012, Nantes, France; CHU de Nantes, Nantes, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Redini
authors.affiliation: INSERM, UMR 957, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France; Equipe LIGUE Nationale Contre le Cancer 2012, Nantes, France; CHU de Nantes, Nantes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use*; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D000068877:Imatinib Mesylate; D007121:Immunocompetence / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects; D012516:Osteosarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020169:Caspases