title: The dual Aurora kinase inhibitor ZM447439 prevents anaplastic thyroid cancer cell growth and tumorigenicity.
abstract: The anaplastic thyroid cancer (ATC) is among the most aggressive human tumors which fail to respond to all the currently available therapeutic approaches. As a consequence most patients die within a few months from diagnosis. In the present preclinical study, the effects of the ZM447439, a functional inhibitor of Aurora kinases, on the growth and tumorigenicity of a panel of ATC derived cell lines (CAL-62, 8305C, 8505C and BHT-101) were evaluated. The treatment of the different ATC cells with ZM447439 inhibited proliferation in a time- and dose-dependent manner, with IC50 comprised between 0.5 mM and 5 mM. Moreover, the drug remarkably impaired the formation of colonies in soft agar of all the cell lines. Consistently with Aurora inhibition, immunofluorescence and immunoblotting experiments demonstrated that Aurora auto-phosphorylation following drug treatment was completely abrogated, and treated cells were characterized by the presence of multiple spindles with short microtubules. In the same experiments we observed the loss of histone H3 phosphorylation on Ser10, specifically due to Aurora-B, after ZM447439 treatment. Time-lapse videomicroscopy and flow cytometric analysis demonstrated that in presence of ZM447439 the cells were able to enter mitosis but not to complete it, becoming polyploid. Almost all the ATC cell lines studied showed increased apoptosis after only 48 h of treatment. In conclusion, our data demonstrate that ZM447439 is effective in reducing cell growth and tumorigenicity of different ATC derived cell lines, and further investigations are needed to exploit its potential therapeutic value for ATC treatment.
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Baldini
authors.forename: C
authors.initials: C
authors.lastname: Tuccilli
authors.forename: N
authors.initials: N
authors.lastname: Prinzi
authors.forename: S
authors.initials: S
authors.lastname: Sorrenti
authors.forename: A
authors.initials: A
authors.lastname: Antonelli
authors.forename: L
authors.initials: L
authors.lastname: Gnessi
authors.forename: A
authors.initials: A
authors.lastname: Catania
authors.forename: C
authors.initials: C
authors.lastname: Moretti
authors.forename: R
authors.initials: R
authors.lastname: Mocini
authors.forename: G
authors.initials: G
authors.lastname: Carbotta
authors.forename: S
authors.initials: S
authors.lastname: Morrone
authors.forename: S
authors.initials: S
authors.lastname: Persechino
authors.forename: A
authors.initials: A
authors.lastname: Redler
authors.forename: E
authors.initials: E
authors.lastname: De Antoni
authors.forename: M
authors.initials: M
authors.lastname: D' Armiento
authors.forename: S
authors.initials: S
authors.lastname: Ulisse
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors*; D001549:Benzamides / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D064096:Aurora Kinase A; D064107:Aurora Kinase B