Cytotoxic effects of high concentrations of sodium ascorbate on human myeloid cell lines.
The effect of high doses of intravenous (sodium) ascorbate (ASC) in the treatment of cancer has been controversial although there is growing evidence that ASC in high (pharmacologic) concentrations induces dose-dependent pro-apoptotic death of tumor cells, in vitro. Very few data are available on the role of ASC in the treatment of acute myeloid leukemia (AML). Ascorbate behaves as an antioxidant at low (physiologic), and as pro-oxidant at pharmacologic, concentrations, and this may account for the differences reported in different experimental settings, when human myeloid cell lines, such as HL60, were treated with ASC. Considering the myeloid origin of HL60 cells, and previous literature reports showing that some cell lines belonging to the myeloid lineage could be sensitive to the pro-apoptotic effects of high concentrations of ASC, we investigated in more details the effects of high doses (0.5 to 7 mM) of ASC in vitro, on a variety of human myeloid cell lines including the following: HL60, U937, NB4, NB4-R4 (retinoic acid [RA]-resistant), NB4/AsR (ATO-resistant) acute promyelocytic leukemia (APL)-derived cell lines, and K562 as well as on normal CD34+ progenitors derived from human cord blood. Our results indicate that all analyzed cell lines including all-trans retinoic acid (ATRA)- and arsenic trioxide (ATO)-resistant ones are highly sensitive to the cytotoxic, pro-oxidant effects of high doses of ASC, with an average 50 % lethal concentration (LC50) of 3 mM, depending on cell type, ASC concentration, and time of exposure. Conversely, high doses of ASC neither did exert significant cytotoxic effects nor impaired the differentiation potential in cord blood (CB) CD34+ normal cells. Since plasma ASC concentrations within the millimolar (mM) range can be easily and safely reached by intravenous administration, we conclude that phase I/II clinical trials using high doses of ASC should be designed for patients with advanced/refractory AML and APL.
Department of Medical, Surgical and Neurological Sciences, University of Siena, Polo Scientifico San Miniato, Via A. Moro 2, 53100, Siena, Italy. mastrangelod10@gmail.com.
Domenico
D
Mastrangelo
Department of Medical, Surgical and Neurological Sciences, University of Siena, Polo Scientifico San Miniato, Via A. Moro 2, 53100, Siena, Italy.
Lauretta
L
Massai
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.|Santa Lucia Foundation, Via del Fosso di Fiorano, 00143, Rome, Italy.
Francesco
F
Lo Coco
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.|Santa Lucia Foundation, Via del Fosso di Fiorano, 00143, Rome, Italy.
Nélida Inés
NI
Noguera
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.|Santa Lucia Foundation, Via del Fosso di Fiorano, 00143, Rome, Italy.
Loredana
L
Borgia
Pescara Cell Factory Foundation Onlus, Corso Vittorio Emanuele II n. 346, 65122, Pescara, Italy.
Giuseppe
G
Fioritoni
Pescara Cell Factory Foundation Onlus, Corso Vittorio Emanuele II n. 346, 65122, Pescara, Italy.
Anna
A
Berardi
Pescara Cell Factory Foundation Onlus, Corso Vittorio Emanuele II n. 346, 65122, Pescara, Italy.
Antonio
A
Iacone
Department of Medical, Surgical and Neurological Sciences, University of Siena, Polo Scientifico San Miniato, Via A. Moro 2, 53100, Siena, Italy.
Michela
M
Muscettola
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
Elvira
E
Pelosi
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
Germana
G
Castelli
Pescara Cell Factory Foundation Onlus, Corso Vittorio Emanuele II n. 346, 65122, Pescara, Italy.
Ugo
U
Testa
Department of Medical, Surgical and Neurological Sciences, University of Siena, Polo Scientifico San Miniato, Via A. Moro 2, 53100, Siena, Italy.
Francesco
F
Di Pisa
Department of Medical, Surgical and Neurological Sciences, University of Siena, Polo Scientifico San Miniato, Via A. Moro 2, 53100, Siena, Italy.
Giovanni
G
Grasso
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000494:pharmacology*; D002460:Cell Line; D003603:Cytotoxins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020014:K562 Cells; D022423:Myeloid Cells / Q000187:drug effects* / Q000502:physiology; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D020298:U937 Cells
D000970:Antineoplastic Agents; D003603:Cytotoxins; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D001205:Ascorbic Acid
Ascorbic acid; Oxidative stress; Reactive oxygen species; Redox chemotherapy; Sodium ascorbate; Vitamin C