Journal
MOLECULAR CANCER THERAPEUTICS
Volume 11, Issue 3, Pages 763-774Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-11-0623
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Funding
- NIH
- VICTR from Vanderbilt CTSA [UL1 RR024975, R01CA131225]
- Vanderbilt SPORE in Gastrointestinal Cancer [P50 CA95103]
- Vanderbilt Ingram Cancer Center [P30 CA68485]
- Vanderbilt Digestive Disease Research Center [DK058404]
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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 mu mol/L MLN8237 (P < 0.05). This effect was further enhanced in combination with 2.5 mu mol/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 TAp73 beta, 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. Mol Cancer Ther; 11(3); 763-74. (C) 2012 AACR.
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