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Okabe S, Tauchi T, Tanaka Y, et al. 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 Int. 2013;13(1):32doi: 10.1186/1475-2867-13-32.
Okabe, S., Tauchi, T., Tanaka, Y., Kimura, S., Maekawa, T., & Ohyashiki, K. (2013). 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, 13(1), 32. https://doi.org/10.1186/1475-2867-13-32
Okabe, Seiichi, et al. "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 vol. 13,1 (2013): 32. doi: https://doi.org/10.1186/1475-2867-13-32
Okabe S, Tauchi T, Tanaka Y, Kimura S, Maekawa T, Ohyashiki K. 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 Int. 2013 Apr 04;13(1):32. doi: 10.1186/1475-2867-13-32. PMID: 23556431; PMCID: PMC3635933.
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Cancer Cell Int. 2013 Apr 04;13(1):32. doi: 10.1186/1475-2867-13-32.

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

Seiichi Okabe, Tetsuzo Tauchi, Yuko Tanaka, Shinya Kimura, Taira Maekawa, Kazuma Ohyashiki

Affiliations

  1. First Department of Internal Medicine, Tokyo Medical University, Tokyo 160-0023, Japan. [email protected].

PMID: 23556431 PMCID: PMC3635933 DOI: 10.1186/1475-2867-13-32

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.

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