Extracellular Adenine Nucleotides and Adenosine Modulate the Growth and Survival of THP-1 Leukemia Cells

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.

Neuroprotective Actions of Different Exogenous Nucleotides in H2O2-Induced Cell Death in PC-12 Cells

“…Our findings are in line with those of previous studies. In addition, our results further support the idea that NTs reduce DNA damage [ 24 , 25 ] and cell apoptosis [ 26 , 27 ], and promote cell proliferation [ 28 , 29 ].…”

Purinergic signaling and purine base metabolism at the crossroads between immunity, metabolism, and cancer: A review

“…In contrast to solid tumors, purinergic signaling in hematological malignancies has shown both tumor‐suppressing and tumor‐promoting effects. When THP‐1, a human leukemia monocytic cell line, is treated with adenosine derivatives, there is a decrease in leukemia cell growth and survival 137 . Conversely, the ATP/P2 × 7 axis increases acute myeloid leukemia (AML) leukemia burden which could be therapeutically targeted using a P2 × 7 receptor antagonist to reduce AML growth in mice 138 , 139 .…”

“…When THP-1, a human leukemia monocytic cell line, is treated with adenosine derivatives, there is a decrease in leukemia cell growth and survival. 137 Conversely, the ATP/P2 × 7 axis increases acute myeloid leukemia (AML) leukemia burden which could be therapeutically targeted using a P2 × 7 receptor antagonist to reduce AML growth in mice. 138,139 What is clear from published studies is that purinergic signaling impacts the development of blood cancers; however, we are just beginning to scratch the surface in our understanding of this relationship.…”

Generation of a Retargeted Oncolytic Herpes Virus Encoding Adenosine Deaminase for Tumor Adenosine Clearance

“…We adopted THP-1 cell line as a model to assess how the adenosine deaminase encoded by THV_ADA and THV_ADA-SP elicits immunomodulatory activity on an immune cell population. It has been previously demonstrated that extracellular adenosine (eADO) inhibits THP-1 proliferation [62] by signaling through ADO receptors. As previously reported, THP-1 cells showed a medium-to-high expression rate of ADO receptors (Figure 5a) [62].…”

“…It has been previously demonstrated that extracellular adenosine (eADO) inhibits THP-1 proliferation [62] by signaling through ADO receptors. As previously reported, THP-1 cells showed a medium-to-high expression rate of ADO receptors (Figure 5a) [62]. We thus cultured THP-1 cells in media supplemented with increasing concentrations of adenosine (10 µM, 50 µM, 100 µM, 1000 µM, 2000 µM).…”