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Additive effects of vorinostat and MLN8237 in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines

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Summary

Purpose Histone deacetylase (HDAC) inhibitors, such as vorinostat, decrease Aurora kinase activity by a variety of mechanisms. Vorinostat and MLN8237, a selective Aurora A kinase inhibitor, disrupt the spindle assembly and the mitotic checkpoint at different points, suggesting that the combination could have increased antitumor activity. The purpose of this study was to determine the cytotoxicity of vorinostat and MLN8237 in pediatric tumor cell lines. Methods Cell survival was measured after 72 h of drug treatment using a modified methyl tetrazolium assay. For drug combination experiments, cells were exposed to medium alone (controls), single drug alone, or to different concentrations of the combination of the two drugs, for a total of 36 concentration pairs per plate. The interaction of the drug combination was analyzed using the universal response surface approach. Results The cells express the target of MLN8237, Aurora A. For each cell line, the single agent IC50 for MLN8237 and for vorinostat was in the clinically relevant range. Both drugs inhibited cell survival in a concentration-dependent fashion. At concentrations of MLN8237 exceeding approximately 1 μM, there was a paradoxical increase in viability signal in all three lines that may be explained by inhibition of Aurora B kinase. The combination of MLN8237 and vorinostat showed additive cytotoxicity in all three cell lines and nearly abrogated the paradoxical increase in survival noted at high single-agent MLN8237 concentrations. Conclusion MLN8237 and vorinostat are active in vitro against cancer cell lines. These results provide important preclinical support for the development of future clinical studies of MLN8237and vorinostat.

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Acknowledgment

This study was supported by the National Cancer Institute K12 Pediatric Clinical Oncology Research Training Program 5K12CA90433-09 (JAM), a Kappa Alpha Theta Faculty Scholar grant (JAM), and a Carousel Faculty Scholar Grant (JAM). This work was presented at the American Association for Cancer Research 102nd Annual Meeting, April 6, 2011, Orlando, FL.

Conflict of interest

J. Ecsedy is an employee of Millennium Pharmaceuticals, Inc.

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Authors and Affiliations

  1. Texas Children’s Cancer Center, Baylor College of Medicine, 1102 Bates Street, Suite 1220, Houston, TX, 77030, USA

    Jodi A. Muscal, Kathleen A. Scorsone, Linna Zhang & Stacey L. Berg

  2. Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA, 02139, USA

    Jeffrey A. Ecsedy

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  1. Jodi A. Muscal
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  2. Kathleen A. Scorsone
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Correspondence to Jodi A. Muscal.

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Muscal, J.A., Scorsone, K.A., Zhang, L. et al. Additive effects of vorinostat and MLN8237 in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines. Invest New Drugs 31, 39–45 (2013). https://doi.org/10.1007/s10637-012-9831-9

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