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...
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| 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 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. |
| doi_str_mv | 10.1371/journal.pone.0090795 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0090795</identifier><identifier>PMID: 24599309</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Apoptosis ; Benzamides - pharmacology ; Benzamides - therapeutic use ; Biology ; Bone cancer ; Caspases - metabolism ; Cell Cycle Checkpoints - drug effects ; Cell death ; Cell Death - drug effects ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Chemotherapy ; Disease Models, Animal ; Disease Progression ; Dosage and administration ; Health aspects ; Humans ; Imatinib Mesylate ; Immunocompetence ; Immunocompetence - drug effects ; Inhibitor drugs ; Leukemia ; Male ; Medicine ; Mice ; Mice, Inbred C57BL ; Mitosis - drug effects ; Osteosarcoma ; Osteosarcoma - drug therapy ; Osteosarcoma - enzymology ; Osteosarcoma - pathology ; Piperazines - pharmacology ; Piperazines - therapeutic use ; Preventive medicine ; Proto-Oncogene Proteins c-akt - metabolism ; Pyrimidines - pharmacology ; Pyrimidines - therapeutic use ; Rats ; Receptor, Platelet-Derived Growth Factor alpha - metabolism ; Sarcoma ; Signal Transduction - drug effects ; Targeted cancer therapy ; TOR Serine-Threonine Kinases - metabolism ; Tumors ; Tyrosine</subject><ispartof>PloS one, 2014-03, Vol.9 (3), p.e90795</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Gobin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Gobin et al 2014 Gobin et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-990f7d4c09fe4d1a6b3c6e51af4094094097178c95ded5e475bd4c38aab287bb3</citedby><cites>FETCH-LOGICAL-c692t-990f7d4c09fe4d1a6b3c6e51af4094094097178c95ded5e475bd4c38aab287bb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944320/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944320/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24599309$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Rutteman, Gerard Roel</contributor><creatorcontrib>Gobin, Bérengère</creatorcontrib><creatorcontrib>Moriceau, Gatien</creatorcontrib><creatorcontrib>Ory, Benjamin</creatorcontrib><creatorcontrib>Charrier, Céline</creatorcontrib><creatorcontrib>Brion, Régis</creatorcontrib><creatorcontrib>Blanchard, Frederic</creatorcontrib><creatorcontrib>Redini, Françoise</creatorcontrib><creatorcontrib>Heymann, Dominique</creatorcontrib><title>Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models</title><title>PloS one</title><addtitle>PLoS One</addtitle><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). 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24599309</pmid><doi>10.1371/journal.pone.0090795</doi><tpages>e90795</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-03, Vol.9 (3), p.e90795 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1504543357 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis Benzamides - pharmacology Benzamides - therapeutic use Biology Bone cancer Caspases - metabolism Cell Cycle Checkpoints - drug effects Cell death Cell Death - drug effects Cell Line, Tumor Cell Proliferation - drug effects Chemotherapy Disease Models, Animal Disease Progression Dosage and administration Health aspects Humans Imatinib Mesylate Immunocompetence Immunocompetence - drug effects Inhibitor drugs Leukemia Male Medicine Mice Mice, Inbred C57BL Mitosis - drug effects Osteosarcoma Osteosarcoma - drug therapy Osteosarcoma - enzymology Osteosarcoma - pathology Piperazines - pharmacology Piperazines - therapeutic use Preventive medicine Proto-Oncogene Proteins c-akt - metabolism Pyrimidines - pharmacology Pyrimidines - therapeutic use Rats Receptor, Platelet-Derived Growth Factor alpha - metabolism Sarcoma Signal Transduction - drug effects Targeted cancer therapy TOR Serine-Threonine Kinases - metabolism Tumors Tyrosine |
| title | Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models |
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