Journal
BRITISH JOURNAL OF CANCER
Volume 109, Issue 10, Pages 2607-2618Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2013.643
Keywords
Aurora kinases; osteosarcoma; targeted therapy; drug resistance; VX-680; ZM447439
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Funding
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG10171]
- Istituto Ortopedico Rizzoli
- European Project 'Kids Cancer Kinome' (KCK [037390]
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
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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. Conclusion: 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.
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