Improvement of genetic stability in lymphocytes from Fanconi anemia patients through the combined effect of α-lipoic acid and N-acetylcysteine

Orphanet Journal of Rare Diseases

Beatriz Porto¹  Félix Carvalho⁵  José Barbot⁴  Cristina Gonçalves²  Ana Paula Fernandes³  Rosa Sousa¹  Filipa Ponte¹ 

[1] Cytogenetics Laboratory, Department of Microscopy, Institute of Biomedical Sciences Abel Salazar (ICBAS), Porto, Portugal;Service of Hematology of Hospital Center of Porto (CHP), Porto, Portugal;Hemato-oncologic Unity, Hospital São João (HSJ), Porto, Portugal;Unity of Pediatric Hematology of CHP, Porto, Portugal;Chemistry and Technology Network (REQUIMTE), Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal

关键词: Cancer susceptibility;    Bone marrow failure;    Chromosome instability;    N-acetylcysteine;    α-lipoic acid;    Antioxidants;    Oxidative stress;    Fanconi Anemia;   

Others  :  864418
DOI  :  10.1186/1750-1172-7-28

 received in 2012-02-08, accepted in 2012-05-16,  发布年份 2012

【 摘 要 】

Fanconi Anemia (FA) is a rare genetic disorder, characterized by progressive bone marrow failure and increased predisposition to cancer. Despite being highly heterogeneous, all FA patients are hypersensitive to alkylating agents, in particular to 1,2:3,4-diepoxybutane (DEB), and to oxidative damage. Recent studies point to defective mitochondria in FA cells, which is closely related with increased production of reactive oxygen species (ROS) and concomitant depletion of antioxidant defenses, of which glutathione is a well-known biomarker.

The objective of the present work is to evaluate the putative protective effect of α-lipoic acid (α-LA), a mitochondrial protective agent, and N-acetylcysteine (NAC), a direct antioxidant and a known precursor for glutathione synthesis, in spontaneous and DEB-induced chromosome instability (CI) in lymphocyte cultures from FA patients.

For that purpose, lymphocyte cultures from 15 FA patients and 24 healthy controls were pre-treated with 20 μM α-LA, 500 μM NAC and α-LA plus NAC at the same concentrations, and some of them were exposed to DEB (0.05 μg/ml). A hundred metaphases per treatment were scored to estimate the relative frequency of spontaneous and DEB-induced chromosome breakage.

The obtained results revealed that a cocktail of α-LA and NAC can drastically improve the genetic stability in FA lymphocytes in vitro, decreasing CI by 60% and 80% in cultures from FA patients and FA mosaic/chimera patients, respectively. These results suggest that the studied cocktail can be used as a prophylactic approach to delay progressive clinical symptoms in FA patients caused by CI, which can culminate in the delay of the progressive bone marrow failure and early cancer development.

【 授权许可】

   
2012 Ponte et al.; licensee BioMed Central Ltd.

【 图 表 】

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