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 language | English |
|---|---|
| Pages (from-to) | 32550-32565 |
| Number of pages | 16 |
| Journal | Oncotarget |
| Volume | 8 |
| Issue number | 20 |
| DOIs | |
| Publication status | Published - May 16 2017 |
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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 journal › Article
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TY - JOUR
T1 - High-dose ascorbate and arsenic trioxide selectively kill acute myeloid leukemia and acute promyelocytic leukemia blasts in vitro
AU - Noguera, Nélida I
AU - Pelosi, Elvira
AU - Angelini, Daniela F
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
PY - 2017/5/16
Y1 - 2017/5/16
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.
AB - 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.
U2 - 10.18632/oncotarget.15925
DO - 10.18632/oncotarget.15925
M3 - Article
C2 - 28427227
VL - 8
SP - 32550
EP - 32565
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 20
ER -