AML-240: Investigation of the Antitumor Effect of Targeting PI3K-AKT-mTOR Pathway and Histone Deacetylase Enzymes on Acute Myeloid Leukemia Cells

Abstract

<h3>Context:</h3> Histone deacetylase inhibitors (HDACi) have promising anticancer activity for acute myeloid leukemia (AML). The combination of HDACi with small molecules, such as phosphatidylinositol-3-kinase (PI3K) inhibitors, is more effective in treating AML than single treatments. <h3>Objective:</h3> The study aimed to investigate the effects of PI3K/AKT/mTOR pathway inhibition and HDAC activation on cell lines of different AML subgroups and the underlying molecular mechanism. It can also give an idea of the mechanisms leading to the pathogenesis of AML. <h3>Design:</h3> The study was performed on 2 different AML cell lines, MOLM-13 and CMK. MTT cell proliferation assay was used to determine the cytotoxic effects of the PI3K inhibitor LY294002 and HDACi (SAHA + PCI-34051 + tubastatin A) treatment, both alone and in combination, on the indicated cell lines. <h3>Results:</h3> In this study, we checked the effects of PI3K inhibition using LY294002 on MOLM-13 and CMK cells with MTT cell viability assay. LY294002 led to a decrease in both AML cells. After that, we investigated the effect of HDAC inhibition on CMK and MOLM-13 cell lines, and we found that the HDAC inhibitors SAHA, tubastatin A, and PCI-34051 cause a decrease in the proliferation of CMK and MOLM-13 cell lines. We combined LY294002 with SAHA, tubastatin A, and PCI, individually, to show how combination therapy using HDACi and PI3Ki affects the AML cells. While the results demonstrated that combination treatment with LY294002+SAHA decreases cell proliferation by 50% in MOLM-13 cells, CMK cells showed a 25% decrease compared to the control. LY294002+tubastatin A treatment showed 65% and 40% decreases in the cell proliferation of MOLM-13 and CMK cells, respectively. The proliferation of both cell lines decreased by approximately 70% upon treatment with LY294002+PCI-34051 for 48 h. <h3>Conclusions:</h3> The result demonstrated that treatment with LY204002 combined with PCI-34051, SAHA, and tubastatin A significantly affected the proliferation of both MOLM-13 and CMK cells. In conclusion, it is hoped that this combination will lead to a more specific targeted combination therapy that results in the abolition of AML.