High-dose ascorbate and arsenic trioxide selectively kill acute myeloid leukemia and acute promyelocytic leukemia blasts <i>in vitro</i>

Abstract

// N&eacute;lida I. Noguera 1, 2 , Elvira Pelosi 3 , Daniela F. Angelini 4 , Maria Liliana Piredda 1, 2 , Gisella Guerrera 4 , Eleonora Piras 4 , Luca Battistini 4 , Lauretta Massai 5 , Anna Berardi 6 , Gianfranco Catalano 2 , Laura Cicconi 1 , Germana Castelli 3 , Agnese D&rsquo;Angi&ograve; 3 , Luca Pasquini 3 , Grazia Graziani 7 , Giuseppe Fioritoni 6 , Maria Teresa Voso 1 , Domenico Mastrangelo 5 , Ugo Testa 3 , Francesco Lo-Coco 1, 2 1 Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy 2 Santa Lucia Foundation, I.R.C.C.S. Via del Fosso di Fiorano, Rome, Italy 3 Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanit&agrave;, Rome, Italy 4 Neuroimmunology and Flow Cytometry Units, Fondazione Santa Lucia-I.R.C.C.S., Rome, Italy 5 Department of Medical, Surgical and Neurological Sciences, University of Siena, Polo Scientifico San Miniato, Siena, Italy 6 Pescara Cell Factory Foundation Onlus, Pescara, Italy 7 Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy Correspondence to: Francesco Lo-Coco, email: francesco.lo.coco@uniroma2.it Keywords: high-dose ascorbate, arsenic trioxide, acute promyelocytic leukemia, acute myeloid leukemia Received: September 22, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: February 06, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: March 06, 2017 ABSTRACT The use of high-dose ascorbate (ASC) for the treatment of human cancer has been attempted several decades ago and has been recently revived by several in vitro and in vivo studies in solid tumors. We tested the cytotoxic effects of ASC, alone or in combination with arsenic trioxide (ATO) in acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL). Leukemic cell lines and primary blasts from AML and APL patients were treated with graded concentrations of ASC, alone or in association with standard concentration (1 &mu;M) of ATO. The ASC/ATO combination killed myeloid blasts, including leukemic CD34 + cells, while sparing CD34 + progenitors obtained from normal cord blood and bone marrow. Actually, approximately one-third (11/36) of primary AML cases were highly sensitive to the ASC/ATO combination. The mechanism of cell killing appeared to be related to increased oxidative stress and overproduction of ROS in a non-quantitative fashion, which resulted in induction of apoptosis. These effects were reverted by the addition of the antioxidant N-Acetyl-Cysteine (NAC). In the APL NB4 model, ASC induced direct degradation of the PML and PML/RARA proteins via caspase activation, while the transcriptional repressor DAXX was recruited in re-constituted PML nuclear bodies. Our findings encourage the design of pilot studies to explore the potential clinical benefit of ASC alone or in combination with ATO in advanced AML and APL.