New insights into redox response modulation in Fanconi's anemia cells by hydrogen peroxide and glutathione depletors

Paola Cuccarolo, Silvia Viaggi, Paolo Degan

Research output: Contribution to journalArticle

Abstract

Fanconi's anemia (FA) patients face severe pathological consequences. Bone marrow failure, the major cause of death in FA, accounting for as much as 80-90% of FA mortality, appears to be significantly linked to excessive apoptosis of hematopoietic cells induced by oxidative stress. However, 20-25% of FA patients develop malignancies of myeloid origin. A survival strategy for bone marrow and hematopoietic cells under selective pressure evidently exists. This study reports that lymphoblastoid cell lines derived from two FA patients displayed significant resistance to oxidative stress induced by treatments with H 2O2 and various glutathione (GSH) inhibitors that induce production of reactive oxygen species, GSH depletion and mitochondrial membrane depolarization. Among the various GSH inhibitors employed, FA cells appear particularly resistant to menadione (5 μm) and ethacrynic acid (ETA, 50 μm), two drugs that specifically target mitochondria. Even after pre-treatment with buthionine sulfoximine, a GSH synthesis inhibitor that induces enhanced induction of reactive oxygen species, FA cells maintain significant resistance to these drugs. These data suggest that the resistance to oxidative stress and the altered mitochondrial and metabolic functionality found in the FA mutant cells used in this study may indicate the survival strategy that is adopted in FA cells undergoing transformation. The study of redox and mitochondria regulation in FA may be of assistance in diagnosis of the disease and in the care of patients.

Original languageEnglish
Pages (from-to)2479-2494
Number of pages16
JournalFEBS Journal
Volume279
Issue number14
DOIs
Publication statusPublished - Jul 2012

Keywords

  • cytometry
  • Fanconi's anemia
  • glutathione
  • mitochondial membrane polarization
  • redox balance

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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