In vitro Evaluation der Wirkung von Proteasominhibition auf Schilddrüsenkarzinomzellen

Das Schilddrüsenkarzinom ist die häufigste maligne Erkrankung der endokrinen Organsysteme. Während für gut differenzierte Schilddrüsenkarzinome wie das papilläre und follikuläre Karzinom sehr gute Therapieoptionen existieren, die ein 10-Jahresüberleben von bis zu 98 % ermöglichen, versagen diese bei...

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Bibliographic Details
Main Author: Arndt, Tjadina
Contributors: Hoffmann, Sebastian (PD Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2014
Online Access:PDF Full Text
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Among the endocrine malignancies thyroid cancer (TC) is the most common malignant tumor and shows an increasing incidence. For differentiated thyroid cancer like follicular and papillary carcinoma there are standardized treatments by surgery and radioiodine which result in long term survival. The 10-year survival rate is given as 98%. In contrast this therapeutic regime fails at anaplastic thyroid carcinoma (ATC), which is a dedifferentiated thyroid cancer and belongs to the most aggressive malignancies with fatal outcome of only a few months after diagnosis. In face of the poor clinical outcome of ATC-patients, there is a great effort to develop new effective and innovative treatment options like new antitumoral compounds targeting various tumor promoting pathways. One new approach of this targeted therapy is to inhibit the ubiquitin-proteasome pathway representing a major pathway for degradation of intracellular proteins. In this study the effectiveness of Bortezomib (PS-341, Velcade®) was examined on different TC cell lines. Three anaplastic (C643, Hth74 and Kat4), one follicular (FTC133) and one papillary (TPC1) TC cell lines were used. At these TC cell lines antiproliferative, proapoptotic and transcriptional effects of Bortezomib were analyzed in vitro. Bortezomib inhibited proliferation of TC cells with IC50 values at 144 hour between 4 nM and 12 nM, increased caspase-3 activity and induced cell cycle arrest. The NFkB activity was affected differently. The present systematic in vitro study reveals the effectiveness of Bortezomib on ATC cell lines with a significant reduction of cell viability and a proapoptotic activitiy of Bortezomib on TC cell lines. Nevertheless the influence on nuclear transcription remains controversial. Bortezomib is already used as first-line therapy in multiple myeloma and furthermore entered preclinical and clinical studies in solid tumors. Based on the data of the present study, particularly with regard to ATC cell lines, a clinical evaluation of Bortezomib treatment in ATC is warranted and raised new hope of detecting an effective treatment option for ATC, either alone or in combination with other chemotherapeutic agents