title: Combined inhibition of cellular pathways as a future therapeutic option in fatal anaplastic thyroid cancer.
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.
authors.affiliation: Department of Surgery, Philipps-University of Marburg, Baldingerstrasse, 35043, Marburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Wunderlich
authors.forename: Silvia
authors.initials: S
authors.lastname: Roth
authors.forename: Annette
authors.initials: A
authors.lastname: Ramaswamy
authors.forename: Brandon H
authors.initials: BH
authors.lastname: Greene
authors.forename: Cornelia
authors.initials: C
authors.lastname: Brendel
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hinterseher
authors.forename: Detlef K
authors.initials: DK
authors.lastname: Bartsch
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hoffmann
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D064127:Aurora Kinases; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D002277:Carcinoma / Q000188:drug therapy* / Q000503:physiopathology*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007202:Indicators and Reagents; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001552:Benzazepines; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; C518940:MLN8054; D011719:Pyrazines; D042461:Vascular Endothelial Growth Factor A; D000069286:Bortezomib; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D053148:Caspase 3