Abstract
A new approach to improve the effectiveness of acute myeloid leukemia (AML) treatment is to use the properties of purinergic signaling molecules secreted into the bone marrow milieu in response to leukemic cell growth. Therefore, our study aimed to evaluate the effects of extracellular adenine nucleotides and adenosine on the growth and death parameters in the leukemic THP-1 cell line. Cells were exposed to ATP, ADP, AMP, adenosine and nonhydrolyzable analogues of ATP and ADP (ATPγS and ADPβS) in a 1–1000 μM broad concentration range. The basal mRNA expression of the P1 and P2 receptors was evaluated by real-time PCR. Changes in the processes of cell growth and death were assessed by flow cytometry analysis of proliferation, cell cycle and apoptosis. Chemotaxis toward stromal cell-derived factor-1 (SDF-1) was performed using the modified Boyden chamber assay, and chemokine receptor type 4 (CXCR4) surface expression was quantified by flow cytometry. We indicated several antileukemic actions. High micromolar concentrations (100–1000 μM) of extracellular adenine nucleotides and adenosine inhibit the growth of cells by arresting the cell cycle and/or inducing apoptosis. ATP is characterized by the highest potency and widest range of effects, and is responsible for the cell cycle arrest and the apoptosis induction. Compared to ATP, the effect of ADP is slightly weaker. Adenosine mostly has a cytotoxic effect, with the induction of apoptosis. The last studied nucleotide, AMP, demonstrated only a weak cytotoxic effect without affecting the cell cycle. In addition, cell migration towards SDF-1 was inhibited by low micromolar concentrations (10 μM). One of the reasons for this action of ATPγS and adenosine was a reduction in CXCR4 surface expression, but this only partially explains the mechanism of antimigratory action. In summary, extracellular adenine nucleotides and adenosine inhibit THP-1 cell growth, cause death of cells and modulate the functioning of the SDF-1/CXCR4 axis. Thus, they negatively affect the processes that are responsible for the progression of AML and the difficulties in AML treatment.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies characterized by clonal proliferation and the accumulation of morphologically and functionally immature myeloid progenitor cells in bone marrow and peripheral blood [1]
High micromolar concentrations (100–1000 μM) of extracellular ATP, ADP, AMP and adenosine inhibit the growth of THP-1 leukemia cells by arresting the cell cycle and/or inducing apoptosis
Adenosine was characterized by significant cytotoxicity by the induction of apoptosis, but weakly affected the cell cycle
Summary
Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies characterized by clonal proliferation and the accumulation of morphologically and functionally immature myeloid progenitor cells in bone marrow and peripheral blood [1]. It is the most common leukemia in adults; the incidence increases significantly after 45 years of age [2,3]. There has been a continuous increase in the survival rate of patients with AML in the last four decades, they have the lowest survival rates of all types of leukemia, which decreases significantly with age [1,3]. It is necessary to further deepen our knowledge about the complex biology of AML cells and to search for new drug targets that could help to improve long-term outcomes in AML patients
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