Extracellular ATP induces apoptosis through P2X7R activation in acute myeloid leukemia cells but not in normal hematopoietic stem cells
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Valentina Salvestrini1, Stefania Orecchioni2, Giovanna Talarico2, Francesca Reggiani2, Cristina Mazzetti3, Francesco Bertolini2, Elisa Orioli4, Elena Adinolfi4, Francesco Di Virgilio4, Annalisa Pezzi1, Michele Cavo1, Roberto M Lemoli5,*, Antonio Curti1,*
1Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
2European Institute of Oncology, Milan, Italy
3Department Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
4Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
5Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy
*These authors are contributed equally to this work
Valentina Salvestrini, email: email@example.com
Keywords: acute myeloid leukemia (AML), leukemic stem cell (LSC), P2X7R, ATP, apoptosis
Received: May 24, 2016 Accepted: September 25, 2016 Published: December 13, 2016
Recent studies have shown that high ATP levels exhibit direct cytotoxic effects on several cancer cells types. Among the receptors engaged by ATP, P2X7R is the most consistently expressed by tumors. P2X7R 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 P2X7R. Here, we show that P2X7R activation with high dose ATP induces AML blast cells apoptosis. Moreover, P2X7R 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 P2X7R 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.
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