Extracellular ATP induces apoptosis through P2X7R activation in acute myeloid leukemia cells but not in normal hematopoietic stem cells

Abstract

Recent studies have shown that high ATP levels exhibit direct cytotoxic effects on several cancer cells types. Among the receptors engaged by ATP, P2×7R is the most consistently expressed by tumors. P2×7R is an ATP-gated ion channel that could drive the opening of a non-selective pore, triggering cell-death signal. We previously demonstrated that acute myeloid leukemia (AML) cells express high level of P2×7R. Here, we show that P2×7R activation with high dose ATP induces AML blast cells apoptosis. Moreover, P2×7R is also expressed on leukemic stem/progenitor cells (LSCs) which are sensitive to ATP-mediated cytotoxicity. Conversely, this cytotoxic effect was not observed on normal hematopoietic stem/progenitor cells (HSCs). Notably, the antileukemic activity of ATP was also observed in presence of bone marrow stromal cells and its addition to the culture medium enhanced cytosine arabinoside cytotoxicity despite stroma-induced chemoresistance. Xenotransplant experiments confirmed ATP antineoplastic activity in vivo.Overall, our results demonstrate that P2×7R stimulation by ATP induced a therapeutic response in AML at the LSC level while the normal stem cell compartment was not affected. These results provide evidence that ATP would be promising for developing innovative therapy for AML.

Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents

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Small-molecule RL71-triggered excessive autophagic cell death as a potential therapeutic strategy in triple-negative breast cancer

“…The disruption of mitochondrial membrane potential was measured using JC-1 staining by flow cytometry as previously described. 39 , 40 Briefly, cells were incubated with various concentrations of RL71 for 24 h. A potent mitochondrial uncoupling agent CCCP was used as a positive control. Cells were stained with 5 μ g/ml of JC-1 for 20 min at 37 °C and then analyzed for the decrease in red–orange fluorescence using a FACSCalibur flow cytometer (Becton Dickinson, San Jose, CA, USA).…”

The yin and yang functions of extracellular ATP and adenosine in tumor immunity

“…As a major component, eATP in TME is at a high concentration [18,19]. The activation of P2X7R mediates high concentrated ATP-induced tumor cells death directly [20]. Besides the direct inhibition of tumor growth, eATP communicates with other immune cells in TME to regulate tumor growth ( Fig.…”