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
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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