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

Nélida I Noguera, Elvira Pelosi, Daniela F Angelini, Maria Liliana Piredda, Gisella Guerrera, Eleonora Piras, Luca Battistini, Lauretta Massai, Anna Berardi, Gianfranco Catalano, Laura Cicconi, Germana Castelli, Agnese D'Angiò, Luca Pasquini, Grazia Graziani, Giuseppe Fioritoni, Maria Teresa Voso, Domenico Mastrangelo, Ugo Testa, Francesco Lo-Coco

Research output: Contribution to journalArticle

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 μM) 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.

Original languageEnglish
Pages (from-to)32550-32565
Number of pages16
JournalOncotarget
Volume8
Issue number20
DOIs
Publication statusPublished - May 16 2017

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Acute Promyelocytic Leukemia
Acute Myeloid Leukemia
Caspases
Fetal Blood
Transcriptional Activation
Cysteine
Neoplasms
Oxidative Stress
Antioxidants
Bone Marrow
In Vitro Techniques
arsenic trioxide
Apoptosis
Cell Line
Proteins

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High-dose ascorbate and arsenic trioxide selectively kill acute myeloid leukemia and acute promyelocytic leukemia blasts in vitro. / Noguera, Nélida I; Pelosi, Elvira; Angelini, Daniela F; Piredda, Maria Liliana; Guerrera, Gisella; Piras, Eleonora; Battistini, Luca; Massai, Lauretta; Berardi, Anna; Catalano, Gianfranco; Cicconi, Laura; Castelli, Germana; D'Angiò, Agnese; Pasquini, Luca; Graziani, Grazia; Fioritoni, Giuseppe; Voso, Maria Teresa; Mastrangelo, Domenico; Testa, Ugo; Lo-Coco, Francesco.

In: Oncotarget, Vol. 8, No. 20, 16.05.2017, p. 32550-32565.

Research output: Contribution to journalArticle

Noguera, NI, Pelosi, E, Angelini, DF, Piredda, ML, Guerrera, G, Piras, E, Battistini, L, Massai, L, Berardi, A, Catalano, G, Cicconi, L, Castelli, G, D'Angiò, A, Pasquini, L, Graziani, G, Fioritoni, G, Voso, MT, Mastrangelo, D, Testa, U & Lo-Coco, F 2017, 'High-dose ascorbate and arsenic trioxide selectively kill acute myeloid leukemia and acute promyelocytic leukemia blasts in vitro', Oncotarget, vol. 8, no. 20, pp. 32550-32565. https://doi.org/10.18632/oncotarget.15925
Noguera, Nélida I ; Pelosi, Elvira ; Angelini, Daniela F ; Piredda, Maria Liliana ; Guerrera, Gisella ; Piras, Eleonora ; Battistini, Luca ; Massai, Lauretta ; Berardi, Anna ; Catalano, Gianfranco ; Cicconi, Laura ; Castelli, Germana ; D'Angiò, Agnese ; Pasquini, Luca ; Graziani, Grazia ; Fioritoni, Giuseppe ; Voso, Maria Teresa ; Mastrangelo, Domenico ; Testa, Ugo ; Lo-Coco, Francesco. / High-dose ascorbate and arsenic trioxide selectively kill acute myeloid leukemia and acute promyelocytic leukemia blasts in vitro. In: Oncotarget. 2017 ; Vol. 8, No. 20. pp. 32550-32565.
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AU - Piredda, Maria Liliana

AU - Guerrera, Gisella

AU - Piras, Eleonora

AU - Battistini, Luca

AU - Massai, Lauretta

AU - Berardi, Anna

AU - Catalano, Gianfranco

AU - Cicconi, Laura

AU - Castelli, Germana

AU - D'Angiò, Agnese

AU - Pasquini, Luca

AU - Graziani, Grazia

AU - Fioritoni, Giuseppe

AU - Voso, Maria Teresa

AU - Mastrangelo, Domenico

AU - Testa, Ugo

AU - Lo-Coco, Francesco

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N2 - 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 μM) 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.

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