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Endocrine
Published in: Endocrine 3/2012

01-12-2012 | Original Article

Combined inhibition of cellular pathways as a future therapeutic option in fatal anaplastic thyroid cancer

Authors: Annette Wunderlich, Silvia Roth, Annette Ramaswamy, Brandon H. Greene, Cornelia Brendel, Ulrike Hinterseher, Detlef K. Bartsch, Sebastian Hoffmann

Published in: Endocrine | Issue 3/2012

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Abstract

Conventional treatment by surgery, radioiodine, and thyroxin-suppressive therapy often fails to cure anaplastic thyroid cancer (ATC). Therefore several attempts have been made to evaluate new therapy options by use of “small molecule inhibitors”. ATC was shown to respond to monotherapeutic proteasome and Aurora kinase inhibition in vitro as well as in xenotransplanted tumor cells. Aim of this study was to evaluate the effect of combined treatment targeting the ubiquitin–proteasome system by bortezomib and Aurora kinases by use of MLN8054. Three ATC cell lines (Hth74, C643, and Kat4.1) were used. The antiproliferative effect of combined treatment with bortezomib and MLN8054 was assessed by MTT-assay and cell cycle analysis (FACS). Proapoptotic effects were evaluated by measurement of Caspase-3 activity, and effects on VEGF secretion were analyzed by ELISA. Compared to mono-application combined treatment with bortezomib and MLN8054 resulted in a further decrease of cell density, whereas antagonizing effects were found regarding cell cycle progression. Caspase-3 activity was increased up to 2.7- and 14-fold by mono-application of MLN8054 and bortezomib, respectively. When the two drugs were used in combination, a further enhancement of Caspase-3 activity was achieved, depending on the cell line. VEGF secretion was decreased following bortezomib treatment and remained unchanged by MLN8054. Only in C643 cells, the bortezomib-induced down-regulation was enhanced when MLN8054 was applied simultaneously. In conclusion, our data demonstrate that targeting the proteasome and Aurora kinases simultaneously results in additional antitumoral effects in vitro, especially regarding cell growth and induction of apoptosis. The efficacy of this therapeutic approach remains to be revised by in vivo and clinical application.
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Metadata
Title
Combined inhibition of cellular pathways as a future therapeutic option in fatal anaplastic thyroid cancer
Authors
Annette Wunderlich
Silvia Roth
Annette Ramaswamy
Brandon H. Greene
Cornelia Brendel
Ulrike Hinterseher
Detlef K. Bartsch
Sebastian Hoffmann
Publication date
01-12-2012
Publisher
Springer US
Published in
Endocrine / Issue 3/2012
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-012-9665-4

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