antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression抗坏血酸的抗增殖作用与抑制相关基因的细胞周期进程所必需的.pdf

Antiproliferative Effect of Ascorbic Acid Is Associated with the Inhibition of Genes Necessary to Cell Cycle Progression 1 1 1 2 2 ´ 1 Sophie Belin , Ferdinand Kaya , Ghislaine Duisit , Sarah Giacometti , Joseph Ciccolini , Michel Fontes * ´ ´ ´ 1 EA 4263, Therapy of Genetic Disorder, Faculte de Medecine de la Timone, Marseille, France, 2 UPRES EA 3286, Laboratory of Pharmacokinetic and Toxicokinetic, Faculte de Pharmacie, Marseille, France Abstract Background: Ascorbic acid (AA), or Vitamin C, is most well known as a nutritional supplement with antioxidant properties. Recently, we demonstrated that high concentrations of AA act on PMP22 gene expression and partially correct the Charcot- Marie-Tooth disease phenotype in a mouse model. This is due to the capacity of AA, but not other antioxidants, to down- modulate cAMP intracellular concentration by a competitive inhibition of the adenylate cyclase enzymatic activity. Because of the critical role of cAMP in intracellular signalling, we decided to explore the possibility that ascorbic acid could modulate the expression of other genes. Methods and Findings: Using human pangenomic microarrays, we found that AA inhibited the expression of two categories of genes necessary for cell cycle progression, tRNA synthetases and translation initiation factor subunits. In in vitro assays, we demonstrated that AA induced the S-phase arrest of proliferative normal and tumor cells. Highest concentrations of AA leaded to necrotic cell death. However, quiescent cells were not susceptible to AA toxicity, suggesting the blockage of prote