Document Detail


The aurora kinase A inhibitor MLN8237 enhances cisplatin-induced cell death in esophageal adenocarcinoma cells.
MedLine Citation:
PMID:  22302096     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Esophageal adenocarcinomas are poorly responsive to chemotherapeutics. This study aimed to determine the levels of Aurora kinase A (AURKA) and the therapeutic potential of MLN8237, an investigational AURKA inhibitor, alone and in combination with cisplatin. Using quantitative real-time PCR, we detected frequent AURKA gene amplification (15 of 34, 44%) and mRNA overexpression (37 of 44, 84%) in esophageal adenocarcinomas (P < 0.01). Immunohistochemical analysis showed overexpression of AURKA in more than two-thirds of esophageal adenocarcinoma tissue samples (92 of 132, 70%; P < 0.001). Using FLO-1, OE19, and OE33 esophageal adenocarinoma cell lines, with constitutive AURKA overexpression and mutant p53, we observed inhibition of colony formation with a single treatment of 0.5 μmol/L MLN8237 (P < 0.05). This effect was further enhanced in combination with 2.5 μmol/L cisplatin (P < 0.001). Twenty-four hours after treatment with the MLN8237 or MLN8237 and cisplatin, cell-cycle analyses showed a sharp increase in the percentage of polyploid cells (P < 0.001). This was followed by an increase in the percentage of cells in the sub-G(1) phase at 72 hours, concordant with the occurrence of cell death (P < 0.001). Western blot analysis showed higher induction of TAp73β, PUMA, NOXA, cleaved caspase-3, and cleaved PARP with the combined treatment, as compared with a single-agent treatment. Using xenograft models, we showed an enhanced antitumor role for the MLN8237 and cisplatin combination, as compared with single-agent treatments (P < 0.001). In conclusion, this study shows frequent overexpression of AURKA and suggests that MLN8237 could be an effective antitumor agent, which can be combined with cisplatin for a better therapeutic outcome in esophageal adenocarcinomas.
Authors:
Vikas Sehdev; DunFa Peng; Mohammed Soutto; M Kay Washington; Frank Revetta; Jeffrey Ecsedy; Alexander Zaika; Tilman T Rau; Regine Schneider-Stock; Abbes Belkhiri; Wael El-Rifai
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-02-01
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  11     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-03-08     Completed Date:  2012-07-09     Revised Date:  2013-12-09    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  763-74     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / drug therapy,  genetics,  metabolism
Animals
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Apoptosis Regulatory Proteins / genetics,  metabolism
Aurora Kinase A
Aurora Kinases
Azepines / pharmacology*
Blotting, Western
Cell Cycle Checkpoints / drug effects
Cell Line
Cell Line, Tumor
Cell Survival / drug effects
Cisplatin / pharmacology*
Drug Synergism
Esophageal Neoplasms / drug therapy,  genetics,  metabolism
Esophagus / drug effects,  metabolism,  pathology
Female
Gene Expression / drug effects
Humans
Mice
Mice, Nude
Phosphorylation / drug effects
Protein-Serine-Threonine Kinases / antagonists & inhibitors*,  genetics,  metabolism
Proto-Oncogene Proteins / genetics,  metabolism
Proto-Oncogene Proteins c-bcl-2 / genetics,  metabolism
Pyrimidines / pharmacology*
Reverse Transcriptase Polymerase Chain Reaction
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
DK058404/DK/NIDDK NIH HHS; KL2 RR024977/RR/NCRR NIH HHS; KL2 TR000446/TR/NCATS NIH HHS; P30 CA68485/CA/NCI NIH HHS; P50 CA95103/CA/NCI NIH HHS; R01 CA131225-01A2/CA/NCI NIH HHS; R01 CA138833/CA/NCI NIH HHS; R01CA131225/CA/NCI NIH HHS; TL1 RR024978/RR/NCRR NIH HHS; TL1 TR000447/TR/NCATS NIH HHS; UL1 RR024975/RR/NCRR NIH HHS; UL1 RR024975/RR/NCRR NIH HHS; UL1 TR000445/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Apoptosis Regulatory Proteins; 0/Azepines; 0/BBC3 protein, human; 0/MLN 8237; 0/PMAIP1 protein, human; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrimidines; EC 2.7.11.1/AURKA protein, human; EC 2.7.11.1/Aurka protein, mouse; EC 2.7.11.1/Aurora Kinase A; EC 2.7.11.1/Aurora Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; Q20Q21Q62J/Cisplatin
Comments/Corrections

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