Fanconi's anemia (FA) patients face severe pathological consequences. Bone marrow (BM) failure, the major cause of death in FA accounting for as much as 80-90% of FA mortality, appear significantly linked to excessive apoptosis of hematopoietic cells induced by oxidative stress. However as 20-25% of the FA patients develop malignancies of myeloid origin. A surviving strategy for bone marrow and hematopoietic cells under selective pressure has evidently taken place. This study reports how lymphoblastoid cell lines derived from two FA patients display significant resistance to oxidative stress induced by treatments with H(2) O(2) and different glutathione (GSH) inhibitors which induce ROS, GSH depletion and mitochondrial membrane depolarization (MMD). Among the various GSH inhibitors employed FA cells appear peculiarly resistant to Menadione (5 μM) and Ethacrynic acid (ETA, 50 μM), two drugs which specifically target mitochondria. Even after pre-treatments with Buthionine Sulfoximine (BSO), a GSH synthesis inhibitor which induces enhanced ROS induction, FA cells maintain significant resistance to these stressors. 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 define a survival strategy adopted in FA cells undergoing transformation. The study of red-ox and mitochondria regulation in FA may be of help in the diagnosis of the disease and in the care of the patients.

New insights into red-ox response modulation in Fanconi's anemia cells by hydrogen peroxide and glutathione depletors.

VIAGGI, SILVIA;
2012-01-01

Abstract

Fanconi's anemia (FA) patients face severe pathological consequences. Bone marrow (BM) failure, the major cause of death in FA accounting for as much as 80-90% of FA mortality, appear significantly linked to excessive apoptosis of hematopoietic cells induced by oxidative stress. However as 20-25% of the FA patients develop malignancies of myeloid origin. A surviving strategy for bone marrow and hematopoietic cells under selective pressure has evidently taken place. This study reports how lymphoblastoid cell lines derived from two FA patients display significant resistance to oxidative stress induced by treatments with H(2) O(2) and different glutathione (GSH) inhibitors which induce ROS, GSH depletion and mitochondrial membrane depolarization (MMD). Among the various GSH inhibitors employed FA cells appear peculiarly resistant to Menadione (5 μM) and Ethacrynic acid (ETA, 50 μM), two drugs which specifically target mitochondria. Even after pre-treatments with Buthionine Sulfoximine (BSO), a GSH synthesis inhibitor which induces enhanced ROS induction, FA cells maintain significant resistance to these stressors. 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 define a survival strategy adopted in FA cells undergoing transformation. The study of red-ox and mitochondria regulation in FA may be of help in the diagnosis of the disease and in the care of the patients.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11567/365314
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 13
  • ???jsp.display-item.citation.isi??? 11
social impact