Annals of Hematology

, Volume 94, Issue 11, pp 1807–1816 | Cite as

Cytotoxic effects of high concentrations of sodium ascorbate on human myeloid cell lines

  • Domenico Mastrangelo
  • Lauretta Massai
  • Francesco Lo Coco
  • Nélida Inés Noguera
  • Loredana Borgia
  • Giuseppe Fioritoni
  • Anna Berardi
  • Antonio Iacone
  • Michela Muscettola
  • Elvira Pelosi
  • Germana Castelli
  • Ugo Testa
  • Francesco Di Pisa
  • Giovanni Grasso
Original Article

Abstract

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.

Keywords

Vitamin C Sodium ascorbate Ascorbic acid Redox chemotherapy Reactive oxygen species Oxidative stress 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Domenico Mastrangelo
    • 1
  • Lauretta Massai
    • 1
  • Francesco Lo Coco
    • 2
    • 3
  • Nélida Inés Noguera
    • 2
    • 3
  • Loredana Borgia
    • 2
    • 3
  • Giuseppe Fioritoni
    • 5
  • Anna Berardi
    • 5
  • Antonio Iacone
    • 5
  • Michela Muscettola
    • 1
  • Elvira Pelosi
    • 4
  • Germana Castelli
    • 4
  • Ugo Testa
    • 5
  • Francesco Di Pisa
    • 1
  • Giovanni Grasso
    • 1
  1. 1.Department of Medical, Surgical and Neurological SciencesUniversity of Siena, Polo Scientifico San MiniatoSienaItaly
  2. 2.Department of Biomedicine and PreventionUniversity of Rome Tor VergataRomeItaly
  3. 3.Santa Lucia FoundationRomeItaly
  4. 4.Department of Hematology, Oncology and Molecular MedicineIstituto Superiore di SanitàRomeItaly
  5. 5.Pescara Cell Factory Foundation OnlusPescaraItaly

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