Effects of the Aurora kinase inhibitor VX-680 on anaplastic thyroid cancer-derived cell lines.
Anaplastic thyroid cancers (ATC) are aggressive tumors, which exhibit cell cycle misregulations leading to uncontrolled cellular proliferation and genomic instability. They fail to respond to chemotherapeutic agents and radiation therapy, and most patients die within a few months of diagnosis. In the present study, we evaluated the in vitro effects on ATC cells of VX-680, an inhibitor of the Aurora serine/threonine kinases involved in the regulation of multiple aspects of chromosome segregation and cytokinesis. The effects of VX-680 on proliferation, apoptosis, soft agar colony formation, cell cycle, and ploidy were tested on the ATC-derived cell lines CAL-62, 8305C, 8505C, and BHT-101. Treatment of the different ATC cells with VX-680 inhibited proliferation in a time- and dose-dependent manner, with the IC50 between 25 and 150 nM. The VX-680 significantly impaired the ability of the different cell lines to form colonies in soft agar. Analysis of caspase-3 activity showed that VX-680 induced apoptosis in the different cell lines. CAL-62 cells exposed for 12 h to VX-680 showed an accumulation of cells with > or =4N DNA content. Time-lapse analysis demonstrated that VX-680-treated CAL-62 cells exit metaphase without dividing. Moreover, histone H3 phosphorylation was abrogated following VX-680 treatment. In conclusion, our data demonstrated that VX-680 is effective in reducing cell growth of different ATC-derived cell lines and warrant further investigation to exploit its potential therapeutic value for ATC treatment.
Arlot-Bonnemains
Yannick
Y
CNRS-UMR 6061 Génétique et Développement, IFR 140 GFAS, Faculté de Médecine, Université Rennes 1, 35043 Rennes Cedex, France.
Baldini
Enke
E
Martin
Benedicte
B
Delcros
Jean-Guy
JG
Toller
Matteo
M
Curcio
Francesco
F
Ambesi-Impiombato
Francesco S
FS
D'Armiento
Massimino
M
Ulisse
Salvatore
S
D000362:Agar; D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011003:Ploidies; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D000362:Agar; D064127:Aurora Kinases; D004791:Enzyme Inhibitors; D006657:Histones; D008869:Microtubule-Associated Proteins; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; C120551:TACC3 protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines