Abstract | BACKGROUND: Patients with dedifferentiated or anaplastic thyroid carcinomas currently lack appropriate treatment options. Kinase inhibitors are among the most promising new agents as alternative strategies. The BRAF- and multi- kinase inhibitor, sorafenib, has already shown antitumor effects in thyroid carcinoma patients in a phase III clinical trial. In this study we aim to better characterize molecular effects and efficacy of sorafenib against thyroid carcinoma cells with various histological origins and different BRAF mutational status. Analysis of different signaling pathways affected by sorafenib may contribute to assist a more specific therapy choice with fewer side effects. Twelve thyroid carcinoma cell lines derived from anaplastic, follicular and papillary thyroid carcinomas with wildtype or mutationally activated BRAF were treated with sorafenib. Growth inhibition, cell cycle arrest, cell death induction and inhibition of intracellular signaling pathways were then comprehensively analyzed. METHODS: Cell viability was analyzed by MTT assay, and the cell cycle was assessed by flow cytometry after propidium iodide staining. Cell death was assessed by lactate dehydrogenase liberation assays, caspase activity assays and subG1 peak determinations. Inhibition of intracellular pathways was analyzed in dot blot and western blot analyses. RESULTS: CONCLUSIONS:
Sorafenib inhibited multiple intracellular signaling pathways in thyroid carcinoma cells, which resulted in cell cycle arrest and the initiation of apoptosis. Sorafenib was effective against all thyroid carcinoma cell lines regardless of their tumor subtype origin or BRAF status, confirming that sorafenib is therapeutically beneficial for patients with any subtype of dedifferentiated thyroid cancer. Inhibition of single intracellular targets of sorafenib in thyroid carcinoma cells may allow the development of more specific therapeutic intervention with less side effects.
|
Authors | Martina Broecker-Preuss, Stefan Müller, Martin Britten, Karl Worm, Kurt Werner Schmid, Klaus Mann, Dagmar Fuhrer |
Journal | BMC cancer
(BMC Cancer)
Vol. 15
Pg. 184
(Mar 26 2015)
ISSN: 1471-2407 [Electronic] England |
PMID | 25879531
(Publication Type: Journal Article)
|
Chemical References |
- Antineoplastic Agents
- Phenylurea Compounds
- Protein Kinase Inhibitors
- Niacinamide
- Sorafenib
- Receptor Protein-Tyrosine Kinases
- Proto-Oncogene Proteins B-raf
- Mitogen-Activated Protein Kinases
|
Topics |
- Antineoplastic Agents
(pharmacology)
- Cell Cycle Checkpoints
(drug effects, genetics)
- Cell Death
(drug effects, genetics)
- Cell Line, Tumor
- Cell Survival
(drug effects, genetics)
- Humans
- Mitogen-Activated Protein Kinases
(metabolism)
- Mutation
- Niacinamide
(analogs & derivatives, pharmacology)
- Phenylurea Compounds
(pharmacology)
- Phosphorylation
- Protein Kinase Inhibitors
(pharmacology)
- Proto-Oncogene Proteins B-raf
(genetics)
- Receptor Protein-Tyrosine Kinases
(metabolism)
- Signal Transduction
(drug effects)
- Sorafenib
- Thyroid Neoplasms
(genetics, metabolism, pathology)
|