When observed inhibition exceeds pre dicted inhibition, the two compounds are considered to act synergistically. Background Chronic myeloid leukemia is a hematopoietic dis order characterized by unregulated proliferation of predom inantly myeloid cells in the bone marrow. BCR ABL fusion proteins resulting from the chromosomal transloca tion t cause CML. BCR ABL activity leads to uncontrolled selleck chem inhibitor cell prolifera tion, reduced apoptosis, and malignant expansion of hematopoietic stem cell populations. The ABL tyrosine kin ase inhibitor imatinib has dramatically improved the management and prognosis of patients with CML. However, some patients, particularly those with advanced phase CML, have developed resistance to imatinib. More than 50 distinct point mutations in the kinase do main of BCR ABL have been detected in patients with imatinib resistant CML.

point mutations in this domain are the most frequent cause of acquired imatinib resistance in CML patients. Second generation TKIs, such as dasatinib and nilotinib, have shown promising results in imatinib resistant CML patients, but dasatinib and nilotinib are not effective against CML clones with T315I mutations. Recently, ponatinib was iden tified as a potent oral tyrosine kinase inhibitor and was shown to block native and mutated BCR ABL. Ponatinib is highly active in patients with Ph positive leukemias, includ ing those with BCR ABL T315I mutations. However, alternative strategies against point mutations within the BCR ABL kinase domain are still important to improve the prognosis of CML patients.

Histone deacetylases and histone acetyl transferases are enzymes that regulate chromatin structure and function. Modification of histones plays an important role in the regulation of gene expression. Increased expression of HDACs and disrupted activities of HATs have been observed in several tumor types. HDAC inhibitors are emerging as potent antitumor agents that induce cell cycle arrest, differentiation, and apoptosis in many tumor cells of different origins. HDAC inhibitors represent a new and promising class of antitumor drugs. HDAC inhibitors influence gene expression by en hancing histone acetylation. 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.

This study aimed to examine the activity of the HDAC Batimastat inhibitors vorinostat and pracinostat in vitro, both alone and in combination with an Aurora kinase inhibitor. This study also explored the molecular mecha nisms underlying treatment related cell growth inhib ition and apoptosis in BCR ABL expressing cell lines with point mutations. We found that the combination of HDAC and Aurora kinase inhibitors significantly inhibited cell growth in BCR ABL expressing cells.