The PI3K/AKT Pathway Inhibitor ISC-4 Induces Apoptosis and Inhibits Growth of Leukemia in Preclinical Models of Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia is a heterogeneous disease with a 5-year survival rate of 28.3%, and current treatment options constrained by dose-limiting toxicities. One of the key signaling pathways known to be frequently activated and dysregulated in AML is PI3K/AKT. Its dysregulation is associated with aggressive cell growth and drug resistance. We investigated the activity of Phenybutyl isoselenocyanate (ISC-4) in primary cells obtained from newly diagnosed AML patients, diverse AML cell lines, and normal cord blood cells. ISC-4 significantly inhibited survival and clonogenicity of primary human AML cells without affecting normal cells. We demonstrated that ISC-4-mediated p-Akt inhibition caused apoptosis in primary AML (CD34 +) stem cells and enhanced efficacy of cytarabine. ISC-4 impeded leukemia progression with improved overall survival in a syngeneic C1498 mouse model with no obvious toxic effects on normal myelopoiesis. In U937 xenograft model, bone marrow cells exhibited significant reduction in human CD45 + cells in ISC-4 (∼87%) or AraC (∼89%) monotherapy groups compared to control. Notably, combination treatment suppressed the leukemic infiltration significantly higher than the single-drug treatments (∼94%). Together, the present findings suggest that ISC-4 might be a promising agent for AML treatment.

PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers

“…For example, econazole was a new type of PI3K inhibitor, which inhibited the PI3K/AKT signaling pathway and reversed the resistance of breast cancer cells to doxorubicin 137 . Some studies showed that phenybutyl isoselenocyanate (ISC-4) treatment significantly inhibited PI3K/AKT activation in a dose-dependent manner, and ISC-4-mediated p-Akt inhibition resulted in primary AML (CD34+) stem cell apoptosis and enhanced the efficacy of cytidine 138 . Therefore, PI3K/AKT inhibitors have a central role in the development of novel strategies to overcome MDR.…”

Model guided trait-specific co-expression network estimation as a new perspective for identifying molecular interactions and pathways

“…Constitutive phosphoinositide 3-kinase (PI3K) and AKT signaling are repeatedly reported in AML studies [ 40 ]. However, there is considerable variation in the effect of these pathway inhibitors among AML patients [ 41 ]. However, it might be that the prognostic importance of AKT1 becomes crucial through the interaction with CCNE1 ( Fig 4 , left panel) which plays a key role in cell proliferation [ 42 ].…”

DJ4 Targets the Rho-Associated Protein Kinase Pathway and Attenuates Disease Progression in Preclinical Murine Models of Acute Myeloid Leukemia

“…Mononuclear cells (MNC) were isolated by means of density gradient separation (Ficol-Paque, GE Healthcare Life Sciences, Pittsburgh, PA, USA). Cell lines and primary cells were cultured as previously described [ 51 , 52 ]. DJ4 was synthesized previously at the Organic Synthesis Core of the Penn State College of Medicine, and its high purity (>99%) was quantified via high-performance liquid chromatography and nuclear magnetic spectroscopy [ 50 ].…”

“…The cells were cultured at a constant optimal seeding density in Human Methylcellulose Base Media (R&D Systems, Minneapolis, MN, USA) in a 12-well plate to yield colony outgrowth of 20–100 colonies per well as described previously [ 51 , 52 ]. To test the clonogenic potential, the cells were cultured in the presence of increasing concentrations of DJ4 (0–10 μM) or the DMSO vehicle in a methylcellulose medium for 7–14 days.…”