title: Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines.
abstract: Aurora kinases are serine/threonine kinases that play an essential role in cell division. Their aberrant expression and/or function induce severe mitotic abnormalities, resulting in either cell death or aneuploidy. Overexpression of Aurora kinases is often found in several malignancies, among which is anaplastic thyroid carcinoma (ATC). We have previously demonstrated the in vitro efficacy of Aurora kinase inhibitors in restraining cell growth and survival of different ATC cell lines. In this study, we sought to establish which Aurora might represent the preferential drug target for ATC. To this end, the effects of two selective inhibitors of Aurora-A (MLN8237) and Aurora-B (AZD1152) on four human ATC cell lines (CAL-62, BHT-101, 8305C, and 8505C) were analysed. Both inhibitors reduced cell proliferation in a time- and dose-dependent manner, with IC50 ranges of 44.3-134.2 nM for MLN8237 and of 9.2-461.3 nM for AZD1152. Immunofluorescence experiments and time-lapse videomicroscopy yielded evidence that each inhibitor induced distinct mitotic phenotypes, but both of them prevented the completion of cytokinesis. As a result, poliploidy increased in all AZD1152-treated cells, and in two out of four cell lines treated with MLN8237. Apoptosis was induced in all the cells by MLN8237, and in BHT-101, 8305C, and 8505C by AZD1152, while CAL-62 exposed to AZD1152 died through necrosis after multiple rounds of endoreplication. Both inhibitors were capable of blocking anchorage-independent cell growth. In conclusion, we demonstrated that either Aurora-A or Aurora-B might represent therapeutic targets for the ATC treatment, but inhibition of Aurora-A appears more effective for suppressing ATC cell proliferation and for inducing the apoptotic pathway.
authors: Departments of Experimental MedicineSurgical Sciences'Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyDepartment of Internal MedicineUniversity of Pisa, Pisa, ItalyDepartment of Systems' MedicineUniversity of Rome Tor Vergata, Rome, ItalyDepartment of Surgery 'Pietro Valdoni''Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyCNRS - UMR 6290 (IGDR)University of Rennes 1, Rennes, France.
authors: Enke
authors: E
authors: Baldini
authors: Departments of Experimental MedicineSurgical Sciences'Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyDepartment of Internal MedicineUniversity of Pisa, Pisa, ItalyDepartment of Systems' MedicineUniversity of Rome Tor Vergata, Rome, ItalyDepartment of Surgery 'Pietro Valdoni''Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyCNRS - UMR 6290 (IGDR)University of Rennes 1, Rennes, France.
authors: Chiara
authors: C
authors: Tuccilli
authors: Departments of Experimental MedicineSurgical Sciences'Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyDepartment of Internal MedicineUniversity of Pisa, Pisa, ItalyDepartment of Systems' MedicineUniversity of Rome Tor Vergata, Rome, ItalyDepartment of Surgery 'Pietro Valdoni''Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyCNRS - UMR 6290 (IGDR)University of Rennes 1, Rennes, France.
authors: Natalie
authors: N
authors: Prinzi
authors: Departments of Experimental MedicineSurgical Sciences'Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyDepartment of Internal MedicineUniversity of Pisa, Pisa, ItalyDepartment of Systems' MedicineUniversity of Rome Tor Vergata, Rome, ItalyDepartment of Surgery 'Pietro Valdoni''Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyCNRS - UMR 6290 (IGDR)University of Rennes 1, Rennes, France.
authors: Salvatore
authors: S
authors: Sorrenti
authors: Departments of Experimental MedicineSurgical Sciences'Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyDepartment of Internal MedicineUniversity of Pisa, Pisa, ItalyDepartment of Systems' MedicineUniversity of Rome Tor Vergata, Rome, ItalyDepartment of Surgery 'Pietro Valdoni''Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyCNRS - UMR 6290 (IGDR)University of Rennes 1, Rennes, France.
authors: Alessandro
authors: A
authors: Antonelli
authors: Departments of Experimental MedicineSurgical Sciences'Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyDepartment of Internal MedicineUniversity of Pisa, Pisa, ItalyDepartment of Systems' MedicineUniversity of Rome Tor Vergata, Rome, ItalyDepartment of Surgery 'Pietro Valdoni''Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyCNRS - UMR 6290 (IGDR)University of Rennes 1, Rennes, France.
authors: Lucio
authors: L
authors: Gnessi
authors: Departments of Experimental MedicineSurgical Sciences'Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyDepartment of Internal MedicineUniversity of Pisa, Pisa, ItalyDepartment of Systems' MedicineUniversity of Rome Tor Vergata, Rome, ItalyDepartment of Surgery 'Pietro Valdoni''Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyCNRS - UMR 6290 (IGDR)University of Rennes 1, Rennes, France.
authors: Stefania
authors: S
authors: Morrone
authors: Departments of Experimental MedicineSurgical Sciences'Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyDepartment of Internal MedicineUniversity of Pisa, Pisa, ItalyDepartment of Systems' MedicineUniversity of Rome Tor Vergata, Rome, ItalyDepartment of Surgery 'Pietro Valdoni''Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyCNRS - UMR 6290 (IGDR)University of Rennes 1, Rennes, France.
authors: Costanzo
authors: C
authors: Moretti
authors: Departments of Experimental MedicineSurgical Sciences'Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyDepartment of Internal MedicineUniversity of Pisa, Pisa, ItalyDepartment of Systems' MedicineUniversity of Rome Tor Vergata, Rome, ItalyDepartment of Surgery 'Pietro Valdoni''Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyCNRS - UMR 6290 (IGDR)University of Rennes 1, Rennes, France.
authors: Marco
authors: M
authors: Bononi
authors: Departments of Experimental MedicineSurgical Sciences'Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyDepartment of Internal MedicineUniversity of Pisa, Pisa, ItalyDepartment of Systems' MedicineUniversity of Rome Tor Vergata, Rome, ItalyDepartment of Surgery 'Pietro Valdoni''Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyCNRS - UMR 6290 (IGDR)University of Rennes 1, Rennes, France.
authors: Yannick
authors: Y
authors: Arlot-Bonnemains
authors: Departments of Experimental MedicineSurgical Sciences'Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyDepartment of Internal MedicineUniversity of Pisa, Pisa, ItalyDepartment of Systems' MedicineUniversity of Rome Tor Vergata, Rome, ItalyDepartment of Surgery 'Pietro Valdoni''Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyCNRS - UMR 6290 (IGDR)University of Rennes 1, Rennes, France.
authors: Massimino
authors: M
authors: D'Armiento
authors: Departments of Experimental MedicineSurgical Sciences'Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyDepartment of Internal MedicineUniversity of Pisa, Pisa, ItalyDepartment of Systems' MedicineUniversity of Rome Tor Vergata, Rome, ItalyDepartment of Surgery 'Pietro Valdoni''Sapienza' University of Rome, Viale Regina Elena, 324, 00161 Rome, ItalyCNRS - UMR 6290 (IGDR)University of Rennes 1, Rennes, France salvatore.ulisse@uniroma1.it.
authors: Salvatore
authors: S
authors: Ulisse
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D010755:Organophosphates / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy / Q000378:metabolism
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D051017:Apoptosis Regulatory Proteins; D001381:Azepines; C550258:MLN 8237; D010755:Organophosphates; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; C576917:AURKA protein, human; C576921:AURKB protein, human; D064096:Aurora Kinase A; D064107:Aurora Kinase B
keywords: AZD1152; Aurora inhibitors; Aurora kinases; MLN8237; anaplastic thyroid cancer; cell cycle; therapy