Abstract
BackgroundThe evasion of cell death is one of the hallmarks of cancer, contributing to both tumor progression and resistance to therapy. Dedifferentiated and anaplastic thyroid carcinomas that do not take up radioiodine are resistant to conventional anticancer treatments and patients with these tumors are difficult to treat. BH3 mimetics are a new class of drugs that target anti-apoptotic proteins of the BCL-2 family and promote cell death. The purpose of this study was to analyze the molecular effects of the BH3 mimetic GX15-070 on thyroid carcinoma cell lines and to characterize cell death induced by GX15-070.MethodsA total of 17 cell lines derived from follicular, papillary, and anaplastic thyroid carcinomas were treated with GX15-070. Cell viability was measured with MTT assay while cell cycle phase distribution and subG1 peaks were determined after propidium iodide staining. We assessed cell death via the caspase 3/7 activity, caspase cleavage products, lactate dehydrogenase (LDH) liberation assays, and a LC3 analysis by western blot. Ultrastructural changes were analysed by electron microscopy of GX15-070-treated cells.ResultsAfter GX15-070 treatment, the number of viable cells was decreased in all cell lines examined, with IC50 values ranging from 48nM to 3.25 μM. We observed biochemical markers of autophagic cell death and necrosis like LC3 conversion and LDH release after the GX15-070 treatment. Electron microscopy revealed several common characteristic ultrastructural changes like swelling of mitochondria, dilatation of rough endoplasmic reticulum, membrane blebbing and formation of vacuoles. GX15-070 treatment induced DNA fragmentation detected by subG1-peak induction and an arrest in G1 phase of the cell cycle. Caspase activation after GX15-070 incubation was detected but had no effect on viability of cells.ConclusionsWith these experiments we demonstrated the efficacy of the BH3 mimetic drug GX15-070 acting against dedifferentiated thyroid carcinoma cells of various histological origins by the induction of cell death. GX15-070-treated cells underwent non-classical cell death with signs of apoptosis, autophagy and necrosis in parallel. GX15-07 and related compounds thus may be a new therapeutic option for dedifferentiated thyroid carcinoma of various histological subtypes.
Highlights
The evasion of cell death is one of the hallmarks of cancer, contributing to both tumor progression and resistance to therapy
Based on the importance of B-cell lymphoma (BCL-2) proteins for uncontrolled proliferation and therapy resistance of malignant tumor cells, we studied the effect of the BCL-2 homology (BH3) mimetic GX15-070 on a panel of 17 thyroid carcinoma cell lines
GX15-070 decreased viability of thyroid carcinoma cell lines To investigate the effect of a GX15-070 treatment on the viability of thyroid carcinoma cells that had been derived from different histological subtypes, we treated 17 cell lines from anaplastic, papillary, and follicular thyroid carcinoma with GX15-070 or vehicle for 48 h and assessed the percentage of viable cells compared to controls
Summary
The evasion of cell death is one of the hallmarks of cancer, contributing to both tumor progression and resistance to therapy. Dedifferentiated and anaplastic thyroid carcinomas that do not take up radioiodine are resistant to conventional anticancer treatments and patients with these tumors are difficult to treat. 95 to 97 %) are derived from follicular epithelial cells of the thyroid gland [3, 4]. They are grouped according to pathological criteria into well-. Undifferentiated and anaplastic thyroid carcinomas (ATC) on the other hand have lost the ability to take up radioiodine and are highly aggressive and lethal tumors [7, 8]. Due to the lack of sufficient radioiodine uptake and the aggressive growth pattern, ATCs and dedifferentiated thyroid carcinomas are difficult to treat and have a bad prognosis. In addition to surgery and therapeutic radioiodine treatment, chemotherapy is another therapeutic option for patients with radioiodine-refractory thyroid carcinoma but is less effective with partial response rates of only 25 % or less [9,10,11]
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