Abstract
BackgroundPatients with dedifferentiated and anaplastic thyroid carcinomas that do not take up radioiodine are resistant to chemotherapeutic treatment and external irradiation and thus are difficult to treat. Direct induction of apoptosis is a promising approach in these apoptosis-resistant tumor cells. The BH3 mimetic ABT-737 belongs to a new class of drugs that target anti-apoptotic proteins of the BCL-2 family and facilitate cell death. The purpose of this study was to investigate the effect of ABT-737 alone or in combination with chemotherapeutic drugs on thyroid carcinoma cell lines.MethodsA total of 16 cell lines derived from follicular, papillary, and anaplastic thyroid carcinomas were treated with ABT-737. Cell viability was measured with MTT assay. Cell death was determined by cell cycle phase distribution and subG1 peak analyses, determination of caspase 3/7 activity and caspase cleavage products, lactate dehydrogenase (LDH) liberation assays and LC3 analysis by western blot.ResultsThe number of viable cells was decreased in all cell lines examined after ABT-737 treatment, with IC50 values ranging from 0.73 to 15.6 μM. Biochemical markers of apoptosis like caspase activities, caspase cleavage products and DNA fragmentation determined as SubG1 peak were elevated after ABT-737 treatment, but no LC3 cleavage was induced by ABT-737 indicating no autophagic processes. In combination with doxorubicin and gemcitabine, ABT-737 showed synergistic effects on cell viability.ConclusionsWith these experiments we demonstrated the efficacy of the BH3 mimetic drug ABT-737 against dedifferentiated thyroid carcinoma cells of various histological origins and showed synergistic effects with chemotherapeutic drugs. ABT-737-treated cells underwent an apoptotic cell death. ABT-737 and related BH3 mimetic drugs, alone or in combination, may thus be of value as a new therapeutic option for dedifferentiated thyroid carcinomas.
Highlights
Patients with dedifferentiated and anaplastic thyroid carcinomas that do not take up radioiodine are resistant to chemotherapeutic treatment and external irradiation and are difficult to treat
Based on the importance of B-cell lymphoma (BCL-2) proteins for apoptosis and for the therapy resistance of cancer cells, we studied the effect of the BCL-2 homology (BH3) mimetic ABT-737 on proliferation and cell death induction in different thyroid carcinoma cell lines alone and in combination with chemotherapeutic drugs
ABT‐737 decreased viability of thyroid carcinoma cells Sixteen cell lines from FTC, papillary thyroid carcinoma (PTC) and Anaplastic (undifferentiated) thyroid carcinomas (ATC) were treated with increasing concentrations of ABT-737 or vehicle for 48 h and the percentage of viable cells compared to controls was assessed
Summary
Patients with dedifferentiated and anaplastic thyroid carcinomas that do not take up radioiodine are resistant to chemotherapeutic treatment and external irradiation and are difficult to treat. Differentiated thyroid carcinomas (PDTC) represent an intermediate between ATC and well-differentiated thyroid carcinomas with reduced ability of radioiodine uptake [8]. Besides their aggressive growth, the loss of the ability to take up radioiodine makes both PDTC and ATC difficult to treat, and contributes to the poor patient’s prognosis. Conventional chemotherapeutic treatment is ineffective against aggressive thyroid carcinomas [9, 10] and points to the inability of dedifferentiated thyroid cancer cells to undergo chemotherapy-induced cell death [11]. Facilitating cell death induction in these carcinoma cells is one new therapeutic option
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