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

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 H2O2 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.

Concentration‐dependent metabolic effects of metformin in healthy and Fanconi anemia lymphoblast cells

“…The plot of all physical parameters (forward scatter [FSC] versus side scatter [SSC]) was used to set the gate that delimits debris and aggregates. Ten thousand cells per sample were analyzed (Cuccarolo, Viaggi, & Degan, ).…”

“…GSH was detected by flow cytometry after staining cells with monobromobimane MBB Thermo Fisher Scientific, Italy (Cuccarolo et al, ). When excited at 405 nm, MBB becomes fluorescent after conjugation with intracellular thiols.…”

Ameliorative effect of polyphenols from Padina boergesenii against ferric nitrilotriacetate induced renal oxidative damage: With inhibition of oxidative hemolysis and in vitro free radicals

“…Rats pretreated with extracts showed protective mechanism through significantly elevated level of cellular glutathione, GST, GR, and related enzymes (Eybl et al, ). Elevated GSH is due to increase in GSH radicals to remove up‐regulated ROS level in the kidney then neutralized through forming GSSG (Cuccarolo et al, ). This circumstance is accompanied by the increase in GST, GR, G6PD, and GPX level in PMS (Fernandez‐Checa et al, ).…”

Treatment of FANCA Cells with Resveratrol and N-Acetylcysteine: A Comparative Study

“…The sole increase in GSH reductive potential in FANCA cells appears insufficient to restore a fully functional phenotype. NAC was already reported [21] to be only partially effective in limiting GSH depletion, particularly when employed in drugs targeted to mitochondria.While the negative phenotypic outcomes from the chronic NAC treatment in FANCA cells were almost unexpected its possible detrimental effects are already known. The forced increase in intracellular GSH was indeed reported to induce a paradoxical triggering of mitochondrial oxidative stress [22].…”