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

Cancer Cell International

Kazuma Ohyashiki³  Taira Maekawa²  Shinya Kimura¹  Yuko Tanaka³  Tetsuzo Tauchi³  Seiichi Okabe³ 

[1] Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan;Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan;First Department of Internal Medicine, Tokyo Medical University, Tokyo 160-0023, Japan

关键词: T315I mutation;    Aurora kinase inhibitor;    HDAC inhibitor;   

Others  :  794075
DOI  :  10.1186/1475-2867-13-32

 received in 2012-09-07, accepted in 2013-02-18,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Okabe et al.; licensee BioMed Central Ltd.

【 图 表 】

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