Antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression

• Published in: PloS one Vol. 4; no. 2; p. e4409
• Main Authors: Belin, Sophie, Kaya, Ferdinand, Duisit, Ghislaine, Giacometti, Sarah, Ciccolini, Joseph, Fontés, Michel
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06-02-2009; Public Library of Science (PLoS)
• Subjects: Acids; Adenylate cyclase; Analysis; Animal models; Animals; Antioxidants; Antiproliferatives; Apoptosis; Ascorbic acid; Ascorbic Acid - pharmacology; Biocompatibility; Blockage; Cancer therapies; Cell cycle; Cell Cycle - drug effects; Cell Cycle - genetics; Cell death; Cell division; Cell Division - drug effects; Cell Line; Cell Proliferation - drug effects; Cell Survival - drug effects; Charcot-Marie-Tooth disease; Chemotherapy; Clinical trials; Colon; Colorectal cancer; Cyclic adenosine monophosphate; Cyclic AMP; Deoxyribonucleic acid; Development and progression; Dietary supplements; Disease Progression; DNA; DNA microarrays; Enzymatic activity; Enzymes; Female; Gene expression; Gene Expression Regulation - drug effects; Genes; Genetic aspects; Genetic disorders; Genetics and Genomics/Cancer Genetics; HT29 Cells; Humans; Hybridization; Inhibition; Intracellular; Intracellular signalling; Laboratories; Metastasis; Mice; Mice, Nude; Neoplasms - pathology; Oligonucleotide Array Sequence Analysis; Oncology; Peripheral myelin protein 22; Pharmacology; Polymerase Chain Reaction; Protein biosynthesis; Protein synthesis; Ribosomal DNA; RNA polymerase; Rodents; Toxicity; Transfer RNA; Translation (Genetics); tRNA; Tumor cells; Tumors; Vitamin C
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0004409

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.
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 protein synthesis was mainly detrimental in metabolically-active cells. Using animal models, we found that high concentrations of AA inhibited tumor progression in nude mice grafted with HT29 cells (derived from human colon carcinoma). Consistently, expression of tRNA synthetases and ieF2 appeared to be specifically decreased in tumors upon AA treatment.
AA has an antiproliferative activity, at elevated concentration that could be obtained using IV injection. This activity has been observed in vitro as well in vivo and likely results from the inhibition of expression of genes involved in protein synthesis. Implications for a clinical use in anticancer therapies will be discussed.