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.
Highlights
Acute Myeloid Leukemia (AML) is a highly heterogeneous malignancy
The cell growth of MV4-11 cells was found to be significantly inhibited by ISC-4 treatment with both concentrations at indicated time points (Figure 1B, left panel), extent of inhibition was less significant for OCI-AML3 cells (Figure 1B, right panel)
To test if ISC-4 could enhance the cytotoxic effect of cytarabine, an AML standard of care agent, OCI-AML3 and U937 cells were treated with increasing concentrations of ISC-4 (0.75– 24 μM) and AraC (0.062–4 μM) simultaneously for 24, 48, or 72 h
Summary
Acute Myeloid Leukemia (AML) is a highly heterogeneous malignancy. It is characterized by infiltration of abnormally and poorly differentiated hematopoietic cells in the bone marrow and peripheral blood. Despite recent achievements in AML drug discovery, the 5-year survival rate is 28.3% [1,2,3]. AML arises from malignant transformation of immature hematopoietic stem and progenitor cells (HSPC) following an aberrant and poorly regulated. The increasing frequency of Leukemic Stem Cells (LSC) has been shown at relapse after conventional chemotherapy contributing to increased drug-resistance [5]. All this highlights that there is an urgent need for effective novel therapeutics for AML
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