Additive effects of vorinostat and MLN8237 in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines.
OBJECTIVE
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 IC(50) 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.


CONCLUSIONS
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.
Texas Children's Cancer Center, Baylor College of Medicine, 1102 Bates Street, Suite 1220, Houston, TX 77030, USA. jamuscal@txch.org
Jodi A
JA
Muscal
Kathleen A
KA
Scorsone
Linna
L
Zhang
Jeffrey A
JA
Ecsedy
Stacey L
SL
Berg
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001381:Azepines / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004347:Drug Interactions; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology; D008527:Medulloblastoma / Q000188:drug therapy / Q000201:enzymology; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage*; D000077337:Vorinostat
D000970:Antineoplastic Agents; D001381:Azepines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000077337:Vorinostat; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases