title: Activity of histone deacetylase inhibitors and an Aurora kinase inhibitor in BCR-ABL-expressing leukemia cells: Combination of HDAC and Aurora inhibitors in BCR-ABL-expressing cells.
abstract: BACKGROUND
  The use of imatinib, an ABL tyrosine kinase inhibitor, has led to a dramatic change in the management of BCR-ABL-positive leukemia patients. However, resistance to imatinib mediated by mutations in the BCR-ABL domain has become a major problem in the treatment of these patients.
  
  
  METHODS
  In the present study, we examined the activity of histone deacetylase (HDAC) inhibitors in combination with an Aurora kinase inhibitor in BCR-ABL-expressing cells.
  
  
  RESULTS
  We found the HDAC inhibitors vorinostat and/or pracinostat (SB939) induced apoptosis in BCR-ABL-expressing cells. Additionally, HDAC inhibitors reduced levels of Aurora A and B protein. An Aurora kinase inhibitor, tozasertib (VX-680), inhibited growth, promoted pro-apoptotic activity, reduced the phosphorylation of BCR-ABL and Crk-L, and activated caspase-3 and poly (ADP-ribose) polymerase (PARP) in BCR-ABL-positive cells. Moreover, after treatment with tozasertib, HDAC protein expression was decreased. Combination of vorinostat or pracinostat with tozasertib had a synergistic inhibitory effect on the proliferation of T315I cells. Phosphorylation of Crk-L decreased, and PARP activation increased after treatment with vorinostat or pracinostat and tozasertib. Moreover, combination of vorinostat or pracinostat and tozasertib significantly increased the extent of apoptosis in primary chronic myeloid leukemia cells.
  
  
  CONCLUSIONS
  This study demonstrated that combination of HDAC and Aurora inhibitors was highly effective against BCR-ABL-expressing cells.
authors.affiliation: First Department of Internal Medicine, Tokyo Medical University, Tokyo 160-0023, Japan. okabe@tokyho-med.ac.jp.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Okabe
authors.forename: Tetsuzo
authors.initials: T
authors.lastname: Tauchi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.forename: Taira
authors.initials: T
authors.lastname: Maekawa
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ohyashiki
references.citation: Clin Cancer Res. 2008 Oct 1;14(19):6181-6
references.pmid: 18829496
references.citation: Cancer Lett. 2008 Sep 28;269(1):7-17
references.pmid: 18462867
references.citation: N Engl J Med. 2012 Nov 29;367(22):2075-88
references.pmid: 23190221
references.citation: N Engl J Med. 2002 Feb 28;346(9):645-52
references.pmid: 11870241
references.citation: Oncogene. 2007 Aug 13;26(37):5420-32
references.pmid: 17694083
references.citation: Adv Enzyme Regul. 1984;22:27-55
references.pmid: 6382953
references.citation: Oncogene. 2007 Feb 26;26(9):1351-6
references.pmid: 17322921
references.citation: Stem Cells Dev. 2007 Jun;16(3):503-14
references.pmid: 17610380
references.citation: Ann Oncol. 2011 Nov;22(11):2516-2522
references.pmid: 21385886
references.citation: Semin Hematol. 2010 Oct;47(4):371-80
references.pmid: 20875554
references.citation: Cancer. 2005 Apr 15;103(8):1659-69
references.pmid: 15747376
references.citation: Oncogene. 2007 Aug 13;26(37):5528-40
references.pmid: 17694092
references.citation: Clin Cancer Res. 2006 Dec 15;12(24):7374-9
references.pmid: 17189410
references.citation: Cancer Chemother Pharmacol. 2011 Feb;67(2):305-14
references.pmid: 20386909
references.citation: Blood. 2005 Dec 1;106(12):3948-54
references.pmid: 16105974
references.citation: Ann Intern Med. 2006 Dec 19;145(12):913-23
references.pmid: 17179059
references.citation: Blood. 2005 Jan 15;105(2):474-80
references.pmid: 15345598
references.citation: Oncogene. 2007 Aug 13;26(37):5310-8
references.pmid: 17694074
references.citation: Nat Med. 2004 Mar;10(3):262-7
references.pmid: 14981513
references.citation: Mol Cancer Ther. 2011 Jul;10(7):1207-17
references.pmid: 21586629
references.citation: J Clin Invest. 1978 Oct;62(4):815-23
references.pmid: 308953
references.citation: Clin Cancer Res. 2009 Feb 1;15(3):840-50
references.pmid: 19188154
references.citation: Blood. 2007 Jul 15;110(2):727-34
references.pmid: 17405907
references.citation: Biochem Biophys Res Commun. 2009 Mar 20;380(4):775-9
references.pmid: 19338751
references.citation: Leukemia. 2002 Nov;16(11):2190-6
references.pmid: 12399961
references.citation: Acta Haematol. 2008;119(4):212-7
references.pmid: 18566539
references.citation: Blood Cells Mol Dis. 2006 Mar-Apr;36(2):308-14
references.pmid: 16503409
references.citation: J Clin Oncol. 2010 Oct 10;28(29):4507-12
references.pmid: 20837947