title: Formaldehyde-releasing prodrugs specifically affect cancer cells by depletion of intracellular glutathione and augmentation of reactive oxygen species.
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.
authors.affiliation: Chemistry Department, Bar Ilan University, Ramat Gan, Israel.
authors.forename: Inesa
authors.initials: I
authors.lastname: Levovich
authors.forename: Abraham
authors.initials: A
authors.lastname: Nudelman
authors.forename: Gili
authors.initials: G
authors.lastname: Berkovitch
authors.forename: Lonnie P
authors.initials: LP
authors.lastname: Swift
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Cutts
authors.forename: Don R
authors.initials: DR
authors.lastname: Phillips
authors.forename: Ada
authors.initials: A
authors.lastname: Rephaeli
mesh_terms: D000079:Acetaldehyde / Q000737:chemistry / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005557:Formaldehyde / Q000737:chemistry / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D017382:Reactive Oxygen Species; D005557:Formaldehyde; D005978:Glutathione; D000079:Acetaldehyde; D000111:Acetylcysteine