Mitomycin C and diepoxybutane action mechanisms and FANCC protein functions: further insights into the role for oxidative stress in Fanconi's anaemia phenotype.
Evidence for redox-dependent toxicities of mitomycin C (MMC) and diepoxybutane (DEB), through different mechanisms, has been related to the phenotypic defect(s) of Fanconi's anaemia (FA) cells, due to their excess sensitivity to these agents. Recent data have pointed to interactions of the FANCC protein (encoded by the FA complementation group C gene, FA-C) with NADPH cytochrome P450 reductase and glutathione S-transferase (GST), two activities involved in either triggering or detoxifying reactive intermediates, including xenobiotics and reactive oxygen species. A body of evidence points to: (i) oxygen hypersensitivity of FA cells; (ii) oxygen-dependent MMC and DEB toxicity; (iii) excess oxidative DNA damage in FA cells; and (iv) DEB-induced glutathione depletion and GST inhibition. The available evidence corroborates the previously suggested role for oxidative stress in FA phenotype and disease progression, shedding new light on the redox-dependent mechanisms in MMC and DEB toxicities, and suggesting a direct association of oxidative stress with the primary genetic defect in FA.
Pagano
G
G
Italian National Cancer Institute, G.Pascale Foundation, via M. Semmola,I-80131 Naples, Italy. gbpagano@tin.it.
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004852:Epoxy Compounds / Q000494:pharmacology*; D005199:Fanconi Anemia / Q000378:metabolism*; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology*; D009687:Nuclear Proteins; D018384:Oxidative Stress; D010641:Phenotype; D011506:Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004852:Epoxy Compounds; C497651:FANCC protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins; D016685:Mitomycin; C007366:diepoxybutane