GCRIS

Acute Myeloid Leukemia (AML) is a disease characterized by the accumulation of immature myeloid cells called blasts in the peripheral blood, bone marrow, spleen, and liver, eventually leading to hematopoietic malignancy. In addition to genetic abnormalities, important cellular pathways such as PI3K/AKT/mTOR, Wnt, Notch, STAT3, Hedgehog have been reported to play a role in the pathogenesis of AML. Histone deacetylase (HDAC) inhibitors have promising anticancer activity for AML. In this study, it was aimed to investigate the effect of inhibition of the PI3K/AKT/mTOR pathway and HDAC inhibition on the molecular mechanism underlying this disease using cell lines of different AML subgroups, MOLM-13 and CMK cell lines. For this purpose, the effects of PI3K inhibitor LY294002 and HDAC inhibitors (SAHA, PCI-3501 and Tubastatin A) and their combinations were investigated. Cell proliferation was determined by MTT cell cytotoxicity test and apoptosis rates were determined by Annexin-V/PI double staining method, and the effects of drugs on the cell cycle were determined by PI staining. The level of LC3B protein, a marker of autophagy, was confirmed at the molecular level by western blot. The inhibitors used decreased cell viability at low micromolar concentrations on both cell lines. It was determined that the LY294002+SAHA combination treatment showed a 50% reduction in cell proliferation in MOLM-13 cells and a 25% decrease in CMK cells. LY294002+Tubastatin A treatment has been shown to reduce cell proliferation in MOLM-13 and CMK cells by 65% and 40%, respectively. Our results showed that combinations of LY294002 and HDAC inhibitor resulted in G0/G1 phase arrest in MOLM-13 cells compared to control cells. On the other hand, CMK cells treated with combinations of LY294002+SAHA, LY294002+PCI-3501 and LY294002+Tubastatin A were arrested in G2/M, G2/M and G0/G1 phase, respectively. The effect of the combinations on apoptotic cell death was investigated. LC3B protein expression level was checked as a result of combination therapy. Considering the effects of HDAC enzymes on both AML and different cancers, HDAC inhibition is an important and high-potential target for AML. Therefore, investigation of the PI3K/AKT/mTOR pathway and inhibition of HDACs in different subgroups may provide insight into the mechanisms leading to the pathogenesis of AML. Consequently, it is hoped that this inhibition of PI3K/AKT/mTOR and HDAC will lead to a more specific combination of targeted therapy that results in the abolition of AML.

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