Abstract
BackgroundThe 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.MethodsIn the present study, we examined the activity of histone deacetylase (HDAC) inhibitors in combination with an Aurora kinase inhibitor in BCR-ABL-expressing cells.ResultsWe 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.ConclusionsThis study demonstrated that combination of HDAC and Aurora inhibitors was highly effective against BCR-ABL-expressing cells.
Highlights
The use of imatinib, an ABL tyrosine kinase inhibitor, has led to a dramatic change in the management of BCR-ABL-positive leukemia patients
This study aimed to examine the activity of the histone deacetylase (HDAC) inhibitors vorinostat and pracinostat (SB939) in vitro, both alone and in combination with an Aurora kinase inhibitor
Activity of HDAC inhibitors in BCR-ABL-positive cells HDACs have been identified as novel targets for the treatment of hematologic malignancies, including Ph-positive leukemia
Summary
The use of imatinib, an ABL tyrosine kinase inhibitor, has led to a dramatic change in the management of BCR-ABL-positive leukemia patients. BCR-ABL activity leads to uncontrolled cell proliferation, reduced apoptosis, and malignant expansion of hematopoietic stem cell populations. The ABL tyrosine kinase inhibitor (TKI) imatinib has dramatically improved the highly active in patients with Ph-positive leukemias, including those with BCR-ABL T315I mutations [8]. Alternative strategies against point mutations (i.e., T315I) within the BCR-ABL kinase domain are still important to improve the prognosis of CML patients. Increased expression of HDACs and disrupted activities of HATs have been observed in several tumor types [11]. Because HDAC inhibitors regulate many signaling pathways, cotreatment of HDAC inhibitors with molecular targeted drugs, such as Aurora kinase inhibitors, is a promising strategy against many types of tumors
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