Abrogation of histone deacetylases (HDACs) using Panobinostat increased the sensitivity of chronic chronic myeloid leukemia cells to Imatinib

Abrogation of histone deacetylases (HDACs) using Panobinostat increased the sensitivity of chronic chronic myeloid leukemia cells to Imatinib
sara zehtabche,^1,*
1. Shahid Beheshti University of Medical Sciences
Introduction: Although tyrosine kinase inhibitors (TKIs) improved the treatment process of CML, approximately 30% of patients resist TKIs especially in the accelerated and blast crisis phases of the disease. The acquired escape mutations in the kinase domain of BCR/ABL are the main cause of resistance to the first-line TKI (imatinib). Apart from resistance to TKIs that is mediated mainly by BCR/ABL mutations, a subpopulation of leukemic stem cells may exist in the bone marrow, serving as an alternative source of disease relapse. A mounting body of evidence declared that abnormal epigenetic mechanisms through changing the expression and activity of either HATs or HDACs could disrupt the balance between acetylation and deacetylation of histone or non-histone proteins and thereby endows cancer cells with an abnormal advantage of excessive proliferation.
Methods: In order to evaluate the effect of Panobinostat with Imatinib on CML cells, K562 cells were cultured in RPMI 1640 medium and they were treated with inhibitors. Then cell survival was evaluated using Trypan blue exclusion assay and MTT assay. Apoptotic property of panobinostat-plus-imatinib determined using Annexin V/PI staining.
Results: Treatment with the combination of panobinostat and imatinib, as the first-line tyrosine kinase inhibitor used in CML treatment, was further effective in suppressing cell viability and metabolic activity as compared with either drug alone. The results of the annexin-V binding assay also revealed that the cytotoxic activity of panobinostat-plus-imatinib is mediated through the induction of apoptotic cell death
Conclusion: Due to the pharmacologic safety of panobinostat, our study suggests the beneficial application of this inhibitor in the treatment strategies of CML, either as a single agent or in combination with small molecule inhibitors of oncogenic pathways.
Keywords: Chronic myeloid leukemia; Histone deacetylase (HDAC); HDAC inhibition; Panobinostat; Imatinib;