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Preclinical validation of Aurora kinases-targeting drugs in osteosarcoma
1Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Via di Barbiano 1/10, I-40136 Bologna, Italy.
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.
Insights
Aurora kinases are crucial for cell cycle regulation and emerging cancer targets. Inhibitors VX-680 and ZM447439 show promise for osteosarcoma treatment, particularly VX-680 in combination therapy.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Aurora kinases regulate the cell cycle and are potential therapeutic targets in various human cancers.
- Osteosarcoma is a significant human tumor where Aurora kinases' role warrants investigation.
Purpose of the Study:
- To assess the biological relevance of Aurora kinase-A and -B in osteosarcoma.
- To evaluate the in vitro efficacy of Aurora kinase inhibitors VX-680 and ZM447439 against drug-sensitive and drug-resistant osteosarcoma cell lines.
Main Methods:
- Assessed Aurora kinase-A and -B relevance using osteosarcoma clinical samples and gene silencing via siRNA.
- Tested in vitro efficacy of VX-680 and ZM447439 on multiple osteosarcoma cell lines.
- Investigated drug interactions and resistance mechanisms, including ABCB1/MDR1 overexpression.
Main Results:
- Osteosarcoma cell lines showed high sensitivity to both VX-680 and ZM447439.
- Doxorubicin-resistant lines exhibited decreased sensitivity, linked to ABCB1/MDR1.
- VX-680 demonstrated potential to overcome cross-resistance and enhance conventional chemotherapy efficacy.
Conclusions:
- Aurora kinase-A and -B are viable therapeutic targets for osteosarcoma.
- VX-680 shows potential clinical utility, especially when combined with standard osteosarcoma chemotherapy agents.
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