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

FEBS J. 2012 Jul;279(14):2479-94. doi: 10.1111/j.1742-4658.2012.08629.x. Epub 2012 Jun 8.

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(2) O(2) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Buthionine Sulfoximine / pharmacology
  • Cell Line
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Ethacrynic Acid / pharmacology
  • Fanconi Anemia / metabolism
  • Fanconi Anemia / pathology
  • Flow Cytometry
  • Glutathione / antagonists & inhibitors*
  • Glutathione / metabolism*
  • Humans
  • Hydrogen Peroxide / pharmacology*
  • Jurkat Cells
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / physiology
  • Oxidants / pharmacology
  • Oxidation-Reduction / drug effects
  • Oxidative Stress / drug effects
  • Reactive Oxygen Species / metabolism
  • Vitamin K 3 / pharmacology
  • Vitamins / pharmacology

Substances

  • Antimetabolites, Antineoplastic
  • Oxidants
  • Reactive Oxygen Species
  • Vitamins
  • Buthionine Sulfoximine
  • Vitamin K 3
  • Hydrogen Peroxide
  • Glutathione
  • Ethacrynic Acid