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

Abstract

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.

Targeting Sonic Hedgehog-Associated Medulloblastoma through Inhibition of Aurora and Polo-like Kinases

“…Our data demonstrate that the combination of BI-2536 or VX-680 with chemotherapeutic agents (Vincristine, Cisplatin, or Cyclophosphamide) or radiation is more effective than chemotherapy or radiation alone. Previous studies have shown similar effects of combined treatment of established MB cell lines with chemotherapy or radiation plus Aurk or Plk inhibitors (51–53). Together, these studies suggest that incorporating Aurk or Plk inhibitors into MB therapy might enable a reduction in the doses of chemotherapy/radiotherapy and thereby reduce the long-term side-effects associated with these treatments.…”

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

“…Alisertib synergizes with vorinostat in vitro in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines. (43). …”

Targeting Aurora kinase-A downregulates cell proliferation and angiogenesis in neuroblastoma

“…Specifically, MLN8237 is a second generation, orally bioavailable, selective AURKA inhibitor that has been shown to induce cytotoxicity and cell cycle arrest in multiple myeloma (11), enhance chemosensitivity in esophageal cancer, medulloblastoma, and neuroblastoma (12, 13). Preclinical studies using MLN8237 showed significant in vitro growth inhibition and a positive impact on in vivo event-free survival in several pediatric cancers, including neuroblastoma (14), thus prompting phase I clinical trials (15).…”