Cellular effects of imatinib on medullary thyroid cancer cells, harboring multiple endocrine neoplasia Type 2A and 2B associated RET mutations
Autor: | I. Plaza de Menacho, J.Th.M. Plukker, T. P. Links, Bart J. L. Eggen, Loes J. Drenth-Diephuis, Jan Osinga, J. W. B. de Groot, Robert M.W. Hofstra, Hein Schepers |
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Přispěvatelé: | Groningen Biomolecular Sciences and Biotechnology, Cell Biochemistry, Stem Cell Aging Leukemia and Lymphoma (SALL), Faculteit Medische Wetenschappen/UMCG, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Faculty of Science and Engineering, Molecular Neuroscience and Ageing Research (MOLAR), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE) |
Jazyk: | angličtina |
Rok vydání: | 2006 |
Předmět: |
endocrine system diseases
Apoptosis Multiple Endocrine Neoplasia Type 2a Multiple Endocrine Neoplasia Type 2b Receptor tyrosine kinase Tyrosine-kinase inhibitor Piperazines hemic and lymphatic diseases Medicine Phosphorylation Thyroid cancer GeneralLiterature_REFERENCE(e.g. dictionaries encyclopedias glossaries) biology GASTROINTESTINAL STROMAL TUMORS Cell Cycle Medullary thyroid cancer STI571 Carcinoma Medullary Benzamides Imatinib Mesylate ComputingMethodologies_DOCUMENTANDTEXTPROCESSING GROWTH TYROSINE KINASE INHIBITOR Tyrosine kinase medicine.drug CARCINOMA medicine.drug_class MESYLATE Cell Line Tumor TUMORIGENESIS Humans Thyroid Neoplasms CHRONIC MYELOID-LEUKEMIA neoplasms Cell Proliferation Dose-Response Relationship Drug business.industry Cell growth Proto-Oncogene Proteins c-ret Imatinib IN-VITRO PROTOONCOGENE medicine.disease Pyrimidines Mutation biology.protein Cancer research Surgery business Chronic myelogenous leukemia |
Zdroj: | Surgery, 139(6), 806-814. MOSBY-ELSEVIER |
ISSN: | 0039-6060 |
DOI: | 10.1016/j.surg.2005.10.019 |
Popis: | Background Activating mutations in the RET gene, which encodes a tyrosine kinase receptor, often cause medullary thyroid carcinoma (MTC). Surgical resection is the only curative treatment; no effective systemic treatment is available. We evaluated imatinib, a tyrosine kinase inhibitor currently used to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, as a potential drug for systemic treatment of MTC, in 2 MTC-derived cell lines expressing multiple endocrine neoplasia–associated mutant RET receptors. Methods We determined RET expression and Y1062 phosphorylation using Western blot analysis and quantitative polymerase chain reaction. We determined the effects on cell proliferation by a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, and we used fluorescence-activated cell sorter analysis with annexin V/propidium iodide staining to study imatinib-induced cell-cycle arrest, apoptosis, and cell death. Results Imatinib inhibited RET Y1062 phosphorylation in a dose-dependent manner after 1.5 hours of exposure. After 16 hours both RET Y1062 phosphorylation and protein expression levels were affected. Dose-dependent decreases in cell proliferation of both cell lines after exposure to imatinib with inhibitory concentration of 50% levels of 23 ± 2 μmol/L and 25 ± 4 μmol/L were seen. These values are high, compared with those for chronic myelogenous leukemia and gastrointestinal stromal tumors. We further could show that imatinib induced cell-cycle arrest, and apoptotic and nonapoptotic cell death. Conclusions Imatinib inhibits RET-mediated MTC cell growth affecting RET protein levels in vitro in a dose-dependent manner. The concentration of imatinib necessary to inhibit RET in vitro, however, makes it impossible to conclude that imatinib monotherapy will be a good option for systemic therapy of MTC. |
Databáze: | OpenAIRE |
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