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      Preclinical validation of Aurora kinases-targeting drugs in osteosarcoma

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          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.

          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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          Most cited references24

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          Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores

          The Aurora/Ipl1 family of protein kinases plays multiple roles in mitosis and cytokinesis. Here, we describe ZM447439, a novel selective Aurora kinase inhibitor. Cells treated with ZM447439 progress through interphase, enter mitosis normally, and assemble bipolar spindles. However, chromosome alignment, segregation, and cytokinesis all fail. Despite the presence of maloriented chromosomes, ZM447439-treated cells exit mitosis with normal kinetics, indicating that the spindle checkpoint is compromised. Indeed, ZM447439 prevents mitotic arrest after exposure to paclitaxel. RNA interference experiments suggest that these phenotypes are due to inhibition of Aurora B, not Aurora A or some other kinase. In the absence of Aurora B function, kinetochore localization of the spindle checkpoint components BubR1, Mad2, and Cenp-E is diminished. Furthermore, inhibition of Aurora B kinase activity prevents the rebinding of BubR1 to metaphase kinetochores after a reduction in centromeric tension. Aurora B kinase activity is also required for phosphorylation of BubR1 on entry into mitosis. Finally, we show that BubR1 is not only required for spindle checkpoint function, but is also required for chromosome alignment. Together, these results suggest that by targeting checkpoint proteins to kinetochores, Aurora B couples chromosome alignment with anaphase onset.
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            Limiting the proliferation of polyploid cells.

            Many errors in cell division lead to failure of cytokinesis and the generation of tetraploid cells. Given that tetraploidy can have deleterious consequences, such as genetic instability, we discuss the mechanisms that may have evolved to directly or indirectly prevent the proliferation of these cells.
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              Emerging drugs for high-grade osteosarcoma.

              Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. This review focuses on the most promising therapeutic markers and drugs which may potentially be considered for innovative high-grade OS treatments. The list of drugs and compounds reviewed has been generated by taking into account those which target markers of potential clinical interest for high-grade OS and have been included in Phase I, II or III clinical trials. The literature search covers the last 40 years, starting from the first OS chemotherapy reports of the early 1970s. Particular relevance was given to reports and reviews on new targeted therapies of possible clinical usefulness for high-grade OS. This review gives an updated overview of novel therapeutic approaches which have been or are going to be evaluated in Phase I/II/III clinical studies for high-grade OS. On the basis of the information that has emerged so far, it can be predicted that in the next 5 - 10 years, new agents to be included in innovative treatment strategies for selected subgroups of high-grade OS patients may become available.
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                Author and article information

                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                12 November 2013
                15 October 2013
                : 109
                : 10
                : 2607-2618
                Affiliations
                [1 ]Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute , Via di Barbiano 1/10, I-40136 Bologna, Italy
                [2 ]Department of Human Genetics, Academic Medical Center, University of Amsterdam P.O.Box 22700, 1100 DE Amsterdam, The Netherlands
                Author notes
                Article
                bjc2013643
                10.1038/bjc.2013.643
                3833226
                24129234
                a182aa35-b85e-4b05-8310-775c93233abf
                Copyright © 2013 Cancer Research UK

                From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 14 August 2013
                : 20 September 2013
                : 24 September 2013
                Categories
                Translational Therapeutics

                Oncology & Radiotherapy
                aurora kinases,osteosarcoma,targeted therapy,drug resistance,vx-680,zm447439
                Oncology & Radiotherapy
                aurora kinases, osteosarcoma, targeted therapy, drug resistance, vx-680, zm447439

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