Fe²⁺ as a Physiological and Selective Inhibitor of Vitamin C-Induced Cancer Cell Death

Abstract

High concentrations of ascorbic acid (AA) exert pro-oxidative actions and induce cancer cell death. Recent research on AA toxicity centers on the generation of H₂O₂, but it remains largely unknown why AA is toxic to cancer cells. In the present study we found that low concentrations (< 10 μM) of Fe²⁺ inhibited the toxic effects of AA as well as those of isoascorbic acid (IAA), but not, as far as examined here, on any other types of cell death from H₂O₂, sodium nitroprusside (a NO donor), xanthine+xanthine oxidase (a superoxide inducer), A23187 (a Ca²⁺ ionophore), thapsigargin (an inducer of ER stress), staurosporine (a protein kinase inhibitor), cisplatin (an inducer of DNA damage), 5-fluorouracil (a DNA synthesis inhibitor), or actinomycin D (an RNA synthesis inhibitor) in COS7 cells. Fe²⁺ at concentrations of 1–10 μM inhibited the cell death caused by up to 5 mM AA. However, other divalent metal cations (Mn²⁺, Cr²⁺, Cu²⁺, Zn²⁺, Cd²⁺, and Ni²⁺) were not inhibitory, suggesting that just Fe²⁺, among divalent cations, had such an action on cancer cells at concentrations up to 100 μM. The Fe²⁺-inducedinhibition was commonly observed in COS7 (kidney cancer), Hela (uterine cancer), T98G (glioma), and PC-14 (lung cancer) cells, suggesting the inhibition to be a ubiquitous event among cancer cells. These results suggest that Fe²⁺ is a physiological and selective inhibitor of the AA-induced cancer cell death. The presence of high concentrations (around 30 μM) of Fe²⁺ in vivo might explain unstable effectiveness of AA and IAA infusions against various types of cancers. Conversely, a decrease in Fe²⁺ concentrations in vivo might potently enhance the therapeutic effects of AA infusion against various types of cancers.