title: Preclinical validation of Aurora kinases-targeting drugs in osteosarcoma.
abstract: BACKGROUND
  Aurora kinases are key regulators of cell cycle and represent new promising therapeutic targets in several human tumours.
  
  
  METHODS
  Biological relevance of Aurora kinase-A and -B was assessed on osteosarcoma clinical samples and by silencing these genes with specific siRNA in three human osteosarcoma cell lines. In vitro efficacy of two Aurora kinases-targeting drugs (VX-680 and ZM447439) was evaluated on a panel of four drug-sensitive and six drug-resistant human osteosarcoma cell lines.
  
  
  RESULTS
  Human osteosarcoma cell lines proved to be highly sensitive to both drugs. A decreased drug sensitivity was observed in doxorubicin-resistant cell lines, most probably related to ABCB1/MDR1 overexpression. Both drugs variably induced hyperploidy and apoptosis in the majority of cell lines. VX-680 also reduced in vitro cell motility and soft-agar cloning efficiency. Drug association experiments showed that VX-680 positively interacts with all conventional drugs used in osteosarcoma chemotherapy, overcoming the cross-resistance observed in the single-drug treatments.
  
  
  CONCLUSIONS
  Aurora kinase-A and -B represent new candidate therapeutic targets for osteosarcoma. In vitro analysis of the Aurora kinases inhibitors VX-680 and ZM447439 indicated in VX-680 a new promising drug of potential clinical usefulness in association with conventional osteosarcoma chemotherapeutic agents.
authors.affiliation: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Via di Barbiano 1/10, I-40136 Bologna, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Tavanti
authors.forename: V
authors.initials: V
authors.lastname: Sero
authors.forename: S
authors.initials: S
authors.lastname: Vella
authors.forename: M
authors.initials: M
authors.lastname: Fanelli
authors.forename: F
authors.initials: F
authors.lastname: Michelacci
authors.forename: L
authors.initials: L
authors.lastname: Landuzzi
authors.forename: G
authors.initials: G
authors.lastname: Magagnoli
authors.forename: R
authors.initials: R
authors.lastname: Versteeg
authors.forename: P
authors.initials: P
authors.lastname: Picci
authors.forename: C M
authors.initials: CM
authors.lastname: Hattinger
authors.forename: M
authors.initials: M
authors.lastname: Serra
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D064127:Aurora Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D001549:Benzamides / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D055815:Young Adult; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D000970:Antineoplastic Agents; D064127:Aurora Kinases; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines