|The aurora kinase A inhibitor MLN8237 enhances cisplatin-induced cell death in esophageal adenocarcinoma cells.|
|PMID: 22302096 Owner: NLM Status: MEDLINE|
|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.|
|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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|Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-02-01|
|Title: Molecular cancer therapeutics Volume: 11 ISSN: 1538-8514 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2012 Mar|
|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|
|Languages: eng Pagination: 763-74 Citation Subset: IM|
|APA/MLA Format Download EndNote Download BibTex|
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Apoptosis Regulatory Proteins / genetics, metabolism
Aurora Kinase A
Azepines / pharmacology*
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Cisplatin / pharmacology*
Esophageal Neoplasms / drug therapy, genetics, metabolism
Esophagus / drug effects, metabolism, pathology
Gene Expression / drug effects
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
|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|
|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 18.104.22.168/AURKA protein, human; EC 22.214.171.124/Aurka protein, mouse; EC 126.96.36.199/Aurora Kinase A; EC 188.8.131.52/Aurora Kinases; EC 184.108.40.206/Protein-Serine-Threonine Kinases; Q20Q21Q62J/Cisplatin|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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