title: 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, 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.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Salvestrini
authors.affiliation: European Institute of Oncology, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Orecchioni
authors.affiliation: European Institute of Oncology, Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Talarico
authors.affiliation: European Institute of Oncology, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Reggiani
authors.affiliation: Department Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mazzetti
authors.affiliation: European Institute of Oncology, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertolini
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Orioli
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Adinolfi
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Virgilio
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pezzi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cavo
authors.affiliation: Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.
authors.forename: Roberto M
authors.initials: RM
authors.lastname: Lemoli
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Curti
mesh_terms: D000255:Adenosine Triphosphate / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D058486:Receptors, Purinergic P2X7 / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C546468:P2RX7 protein, human; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate
keywords: ATP; P2X7R; acute myeloid leukemia (AML); apoptosis; leukemic stem cell (LSC)