title: The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell-cycle progression in malignant bladder cancer cells in vitro and in vivo.
abstract: OBJECTIVE
  Despite more than 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluated Aurora kinase A, identified as an upregulated candidate molecule in bladder cancer, as a potential therapeutic target.
  
  
  METHODS
  Gene expression in human bladder cancer samples was evaluated using RNA microarray and quantitative reverse transcriptase PCR. Effects of the Aurora kinase A inhibitor MLN8237 (Millennium) on cell dynamics in malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells were evaluated in vitro and in vivo in a mouse xenograft model.
  
  
  RESULTS
  A set of 13 genes involved in the mitotic spindle checkpoint, including Aurora kinases A and B, were upregulated in human urothelial carcinoma compared with normal urothelium. The Aurora kinase A inhibitor MLN8237 induced cell-cycle arrest, aneuploidy, mitotic spindle failure, and apoptosis in the human bladder cancer cell lines T24 and UM-UC-3. MLN8237 also arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model. Finally, in vitro sequential administration of MLN8237 with either paclitaxel or gemcitabine resulted in synergistic cytotoxic effects in T24 cells.
  
  
  CONCLUSIONS
  Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma and can be exploited with pharmacologic Aurora A inhibition. Given our demonstration of the ability of the Aurora A inhibitor MLN8237 to inhibit growth of bladder cancer in vitro and in vivo, we conclude that Aurora kinase inhibitors warrant further therapeutic investigation in bladder cancer.
authors: Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Ning
authors: N
authors: Zhou
authors: Kamini
authors: K
authors: Singh
authors: Maria C
authors: MC
authors: Mir
authors: Yvonne
authors: Y
authors: Parker
authors: Daniel
authors: D
authors: Lindner
authors: Robert
authors: R
authors: Dreicer
authors: Jeffrey A
authors: JA
authors: Ecsedy
authors: Zhongfa
authors: Z
authors: Zhang
authors: Bin T
authors: BT
authors: Teh
authors: Alexandru
authors: A
authors: Almasan
authors: Donna E
authors: DE
authors: Hansel
mesh_terms: D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001381:Azepines / Q000494:pharmacology* / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016000:Cluster Analysis; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics; D051379:Mice; D009361:Neoplasm Invasiveness; D017239:Paclitaxel / Q000494:pharmacology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology* / Q000633:toxicity; D047368:Tumor Burden / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D001381:Azepines; C550258:MLN 8237; D011743:Pyrimidines; D003841:Deoxycytidine; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel; D000093542:Gemcitabine
references: Urology. 2008 Oct;72(4):873-7
references: 18485461
references: Histol Histopathol. 2010 Nov;25(11):1371-7
references: 20865660
references: CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
references: 22237781
references: Virchows Arch. 2007 Apr;450(4):419-24
references: 17333265
references: Eur J Surg Oncol. 2006 May;32(4):439-44
references: 16517112
references: Clin Cancer Res. 2012 Apr 15;18(8):2210-9
references: 22374334
references: Acta Histochem. 2011 Sep;113(5):514-8
references: 20598352
references: Biochem Biophys Res Commun. 2011 Apr 8;407(2):378-82
references: 21396915
references: Mol Cancer Ther. 2010 Feb;9(2):268-78
references: 20124450
references: Nat Rev Cancer. 2005 Jan;5(1):42-50
references: 15630414
references: J Natl Cancer Inst. 1999 Jul 7;91(13):1160-2
references: 10393726
references: Cancer Res. 1998 Nov 1;58(21):4811-6
references: 9809983
references: Mol Cancer Ther. 2009 Apr;8(4):930-9
references: 19372566
references: Cancer Cell. 2003 Jan;3(1):51-62
references: 12559175
references: Med Res Rev. 2011 Sep;31(5):757-93
references: 20196102
references: Nat Rev Mol Cell Biol. 2003 Nov;4(11):842-54
references: 14625535
references: Nucleic Acids Res. 2002 Jan 1;30(1):207-10
references: 11752295
references: Mol Cell Biol. 2009 Jun;29(11):2935-44
references: 19332559
references: Cell Cycle. 2009 Sep 15;8(18):2984-94
references: 19713763
references: Cancer Res. 2002 Jul 15;62(14):4115-22
references: 12124350
references: Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14188-93
references: 20663956
references: Cancer Res. 2002 Sep 15;62(18):5168-77
references: 12234980
references: Mol Cancer Ther. 2012 Mar;11(3):763-74
references: 22302096
references: Nat Rev Cancer. 2005 Oct;5(10):773-85
references: 16195750
references: Biostatistics. 2003 Apr;4(2):249-64
references: 12925520
references: Bioinformatics. 2004 Feb 12;20(3):307-15
references: 14960456
references: Nucleic Acids Res. 2005 Nov 10;33(20):e175
references: 16284200
references: Nucleic Acids Res. 2003 Feb 15;31(4):e15
references: 12582260
references: Eur J Cancer. 2006 Jan;42(1):50-4
references: 16330205
references: Cell Motil Cytoskeleton. 2004 Dec;59(4):249-63
references: 15499654
references: Biochem Pharmacol. 2011 Apr 1;81(7):881-90
references: 21291867
references: Oncogene. 2006 Nov 16;25(54):7148-58
references: 16715125
references: Urol Oncol. 2013 Apr;31(3):294-302
references: 20843708
references: Cancer Sci. 2010 May;101(5):1204-11
references: 20180813
references: J Clin Oncol. 2006 Dec 10;24(35):5545-51
references: 17158540
references: Am J Pathol. 2010 Jun;176(6):3062-72
references: 20395440
references: Cancer Res. 2010 Jan 15;70(2):440-6
references: 20068163
references: Exp Biol Med (Maywood). 2010 Jul;235(7):814-24
references: 20558835
references: Oncol Res. 1994;6(12):569-79
references: 7787250
references: J Neurooncol. 2012 May;107(3):517-26
references: 22246202
references: J Clin Oncol. 2000 Sep;18(17):3068-77
references: 11001674
references: Int J Cancer. 2012 Dec 1;131(11):2693-703
references: 22488249
references: J Cancer Res Clin Oncol. 2011 Feb;137(2):359-74
references: 20425122
references: J Cell Mol Med. 2011 Oct;15(10):2057-70
references: 21091633
references: Cancer Res. 2008 Nov 1;68(21):8998-9004
references: 18974145
references: Neoplasia. 2009 May;11(5):418-25
references: 19412426
references: Nat Genet. 1998 Oct;20(2):189-93
references: 9771714
references: Genes Dev. 2009 Mar 15;23(6):675-80
references: 19261747
references: Bioinformatics. 2003 Jan 22;19(2):185-93
references: 12538238
references: Blood. 2010 Jun 24;115(25):5202-13
references: 20382844