Evaluation of Aurora kinase inhibition as a new therapeutic strategy in anaplastic and poorly differentiated follicular thyroid cancer.

Abstract

Due to an unfavorable prognosis using the usual therapy, patients with anaplastic thyroid cancer (ATC) are in desperate need of new therapeutic strategies. The objective of this study was to evaluate the effects of MLN8054, an inhibitor of the Aurora serine/threonine kinases, on ATC cells in vitro and on ATC xenografts as a new therapeutic strategy for ATC. Three anaplastic (Hth74, C643, Kat4) and one follicular (FTC133) thyroid cancer cell lines were evaluated in vitro and Kat4 xenografts in vivo. The antiproliferative effect of MLN8054 (0.1-10 μM) on thyroid cancer cells was quantified by sulphorhodamine B-assay. The proapoptotic effect and the effects on the cell cycle were evaluated by flow cytometry after Annexin-V-FITC staining. Further Histone H3 phosphorylation was analysed. In vivo, antiproliferative and antiangiogenic effects were assessed by tumor volume and morphometric analysis following immunohistochemical staining (Ki-67, pHisH3, CD31). Treatment of the different TC cells with MLN8054 inhibited proliferation in a time- and dose-dependent manner, with IC(50) values between 0.1 and 10 μM. Administration of MLN8054 resulted in an increase of apoptotic cells, decreased Histone H3 phosphorylation and induced cell cycle arrest. In vivo, treatment of ATC by MLN8054 resulted in an up to 86% reduced tumor volume and 89% reduced tumor vascularity. In conclusion, our data demonstrated that Aurora kinase inhibition is effective in reducing cell growth and inducing apoptosis of ATC in vitro and tumor growth and vascularity in vivo. Controlled clinical studies on MLN8054 or comparable compounds would be worthwhile to evaluate its potential therapeutic value for treatment of ATC.

• Authors: Annette Wunderlich, Melina Fischer, Torsten Schlosshauer, Annette Ramaswamy, Brandon H Greene, Cornelia Brendel, Dietrich Doll, Detlef Bartsch, Sebastian Hoffmann
• Journal: Cancer science (Cancer Sci) Vol. 102 Issue 4 Pg. 762-8 (Apr 2011) ISSN: 1349-7006 [Electronic] England
• PMID: 21214672 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Japanese Cancer Association.

Chemical References

• Benzazepines
• MLN8054
• RNA, Messenger
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Adenocarcinoma, Follicular
• Animals
• Apoptosis (drug effects)
• Aurora Kinases
• Benzazepines (pharmacology)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Differentiation (drug effects)
• Cell Proliferation (drug effects)
• Humans
• Immunoenzyme Techniques
• Mice
• Mice, Nude
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Thyroid Carcinoma, Anaplastic
• Thyroid Neoplasms (drug therapy, enzymology, pathology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays