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Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models.

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 k... Full description

Journal Title: PloS one 2014, Vol.9(3), p.e90795
Main Author: Gobin, Bérengère
Other Authors: Moriceau, Gatien , Ory, Benjamin , Charrier, Céline , Brion, Régis , Blanchard, Frederic , Redini, Françoise , Heymann, Dominique
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0090795
Link: http://search.proquest.com/docview/1505256060/?pq-origsite=primo
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title: Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models.
format: Article
creator:
  • Gobin, Bérengère
  • Moriceau, Gatien
  • Ory, Benjamin
  • Charrier, Céline
  • Brion, Régis
  • Blanchard, Frederic
  • Redini, Françoise
  • Heymann, Dominique
subjects:
  • Animals–Pharmacology
  • Antineoplastic Agents–Therapeutic Use
  • Benzamides–Pharmacology
  • Caspases–Therapeutic Use
  • Cell Cycle Checkpoints–Metabolism
  • Cell Death–Drug Effects
  • Cell Line, Tumor–Drug Effects
  • Cell Proliferation–Drug Effects
  • Disease Models, Animal–Drug Effects
  • Disease Progression–Drug Effects
  • Humans–Drug Therapy
  • Imatinib Mesylate–Enzymology
  • Immunocompetence–Pathology
  • Male–Pharmacology
  • Mice–Therapeutic Use
  • Mice, Inbred C57bl–Metabolism
  • Mitosis–Pharmacology
  • Osteosarcoma–Therapeutic Use
  • Piperazines–Metabolism
  • Proto-Oncogene Proteins C-Akt–Drug Effects
  • Pyrimidines–Metabolism
  • Rats–Metabolism
  • Receptor, Platelet-Derived Growth Factor Alpha–Metabolism
  • Signal Transduction–Metabolism
  • Tor Serine-Threonine Kinases–Metabolism
  • Antineoplastic Agents
  • Benzamides
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Tor Serine-Threonine Kinases
  • Receptor, Platelet-Derived Growth Factor Alpha
  • Proto-Oncogene Proteins C-Akt
  • Caspases
ispartof: PloS one, 2014, Vol.9(3), p.e90795
description: 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 PDGFR alpha , among 7 other receptors (PDFGFR beta , 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.
language: eng
source:
identifier: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0090795
fulltext: fulltext
issn:
  • 19326203
  • 1932-6203
url: Link


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titleImatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models.
creatorGobin, Bérengère ; Moriceau, Gatien ; Ory, Benjamin ; Charrier, Céline ; Brion, Régis ; Blanchard, Frederic ; Redini, Françoise ; Heymann, Dominique
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ispartofPloS one, 2014, Vol.9(3), p.e90795
identifierE-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0090795
subjectAnimals–Pharmacology ; Antineoplastic Agents–Therapeutic Use ; Benzamides–Pharmacology ; Caspases–Therapeutic Use ; Cell Cycle Checkpoints–Metabolism ; Cell Death–Drug Effects ; Cell Line, Tumor–Drug Effects ; Cell Proliferation–Drug Effects ; Disease Models, Animal–Drug Effects ; Disease Progression–Drug Effects ; Humans–Drug Therapy ; Imatinib Mesylate–Enzymology ; Immunocompetence–Pathology ; Male–Pharmacology ; Mice–Therapeutic Use ; Mice, Inbred C57bl–Metabolism ; Mitosis–Pharmacology ; Osteosarcoma–Therapeutic Use ; Piperazines–Metabolism ; Proto-Oncogene Proteins C-Akt–Drug Effects ; Pyrimidines–Metabolism ; Rats–Metabolism ; Receptor, Platelet-Derived Growth Factor Alpha–Metabolism ; Signal Transduction–Metabolism ; Tor Serine-Threonine Kinases–Metabolism ; Antineoplastic Agents ; Benzamides ; Piperazines ; Pyrimidines ; Imatinib Mesylate ; Tor Serine-Threonine Kinases ; Receptor, Platelet-Derived Growth Factor Alpha ; Proto-Oncogene Proteins C-Akt ; Caspases
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descriptionOsteosarcoma 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 PDGFR alpha , among 7 other receptors (PDFGFR beta , 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.
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titleImatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models.
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