Formaldehyde-releasing prodrugs specifically affect cancer cells by depletion of intracellular glutathione and augmentation of reactive oxygen species

Inesa Levovich, Abraham Nudelman, Gili Berkovitch, Lonnie P. Swift, Suzanne M. Cutts, Don R. Phillips, Ada Rephaeli

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Histone deacetylase inhibitory prodrugs that are metabolized to carboxylic acid(s) and aldehyde(s) possess antineoplastic properties. Formaldehyde- releasing prodrugs were shown to be the most potent. The objective of this study was to gain understanding on the mode of action of these prodrugs in cancer cells. HL-60 and MCF-7 cells in the presence of N-acetylcysteine or glutathione were protected from death induced by formaldehyde-releasing prodrugs but not from death caused by the homologous acetaldehyde-releasing ones. Cell death induced by the former was accompanied by depletion of intracellular glutathione and increased reactive oxygen species that were attenuated by N-acetylcysteine. At fourfold higher concentration, acetaldehyde-releasing prodrugs increased reactive oxygen species that were further augmented by N-acetylcysteine. In HL-60 cells, formaldehyde-releasing prodrugs dissipated the mitochondrial membrane potential and glutathione or N-acetylcysteine restored it. Although acetaldehyde-releasing prodrugs dissipated mitochondrial membrane potential, it occurred at 20-fold greater concentration and was unaffected by the antioxidants. Formaldehyde-releasing prodrugs abrogated c-myc protein expression and elevated c-Jun and H2AX phosphorylation, N-acetylcysteine partially reversed these changes. Herein, we show that formaldehyde-releasing prodrugs diminish the level of glutathione most likely by forming S-formylglutathione adducts resulting in increase of reactive oxygen species followed by signaling events that lead to cancer cells death.

Original languageEnglish
Pages (from-to)471-482
Number of pages12
JournalCancer Chemotherapy and Pharmacology
Volume62
Issue number3
DOIs
StatePublished - Aug 2008

Bibliographical note

Funding Information:
Acknowledgments We thank Ms S. Dominitz for assistance in editing the manuscript; Dr. Luria for help in analyzing the FACS data; This work was supported by grants 542/00–4 from Israel Science Foundation (AR and AN) and the Marcus Center for Pharmaceutical and Medicinal Chemistry (AN).

Keywords

  • Apoptosis
  • Formaldehyde
  • Glutathione
  • HDAC-inhibitors
  • Prodrugs

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