Antiproliferative Effect of Ascorbic Acid Is Associated with the Inhibition of Genes Necessary to Cell Cycle Progression

Abstract

BackgroundAscorbic 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 FindingsUsing 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.ConclusionsAA 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.

Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics

“…Microarray data indicate that primary normal human fibroblasts downregulated 31 genes in response to low-end pharmacologic ascorbate treatment (0.3-0.8 mM) with many of the downregulated genes encoding for either tRNA synthetases or translation initiation factors (3). As suggested by the decreased transcription of these genes, treatment of these cells and several human cancer cell lines with pharmacologic ascorbate concentrations resulted in decreased proliferation.…”

Palmitoyl Ascorbate Liposomes and Free Ascorbic Acid: Comparison of Anticancer Therapeutic Effects Upon Parenteral Administration

“…Doses of free AA were selected as reported in (1,3,4), and PAL dose was selected based on our preliminary results. Our initial studies with mice injected with 4 g/kg of free AA showed signs of toxicity (data not shown); hence, 1 g/kg dose was selected for subsequent studies.…”

“…This present study addresses the question of whether PAL can produce anticancer activity equal to or greater than the activity of AA therapy, which has been reported to decrease tumor growth rates by about 40% in numerous rodent models (1,3,4). Although PAL are being used to deliver ascorbate, the effects of PAL cannot be expected to be identical to those of injected free AA due to differences in delivery dynamics and biochemical behavior.…”

“…and significantly slows the growth of numerous aggressive tumor types (1,3,4). Clinical studies have shown that AA injection is very safe for screened patients (5)(6)(7), and may offer clinical benefit by improving quality of life (8).…”

A biochemical and histopathologic study showing protection and treatment of gentamicin-induced nephrotoxicity in rabbits using vitamin c

“…Vitamin C is a hydrophilic substance (Akturk et al, 2006;Harapanhalli et al, 1996) that acts as a nutritional supplement and is considered to be very essential in preventing scurvy (Belin et al, 2009). It is known to be an outstanding chain-breaking antioxidant as well as a very good free radical scavenger (Premila, 2005).…”