Analysis of High-Dose Ascorbate-Induced Cytotoxicity in Human Glioblastoma Cells and the Role of Dehydroascorbic Acid and Iron.

in Antioxidants (Basel, Switzerland) by Alban Piotrowsky, Markus Burkard, Katharina Hammerschmidt, Hannah K Ruple, Pia Nonnenmacher, Monika Schumacher, Christian Leischner, Susanne Berchtold, Luigi Marongiu, Thomas A Kufer, Ulrich M Lauer, Olga Renner, Sascha Venturelli

TLDR

  • This study looked at how high doses of vitamin C (ascorbate) affected human brain tumor cells. They found that high doses of vitamin C killed the cells and reduced their ability to grow. They also found that adding other substances like magnesium and iron to the vitamin C made it even more effective at killing the cells. The study also looked at how the vitamin C caused the cells to die and found that it was through a process called ferroptosis, which is different from the way cells usually die.

Abstract

Several studies have demonstrated, both in vitro and in animal models, the anti-tumor efficacy of high-dose ascorbate treatment against a variety of tumor entities, including glioblastoma, the most common and aggressive primary malignant brain tumor. The aim of this study was to investigate the effects of high-dose ascorbate as well as dehydroascorbic acid on human glioblastoma cell lines and to evaluate different treatment conditions for the combined administration of ascorbate with magnesium (Mg) and iron (Fe). Intracellular levels of reactive oxygen species and the induction of cell death following ascorbate treatment were also investigated. We demonstrated high cytotoxicity and antiproliferative efficacy of high-dose ascorbate in human glioblastoma cells, whereas much weaker effects were observed for dehydroascorbic acid. Ascorbate-induced cell death was independent of apoptosis. Both the reduction in cell viability and the ascorbate-induced generation of intracellular reactive oxygen species could be significantly increased by incubating the cells with Febefore ascorbate treatment. This work demonstrates, for the first time, an increase in ascorbate-induced intracellular ROS formation and cytotoxicity in human glioblastoma cells by pre-treatment of the tumor cells with ferric iron, as well as caspase-3 independence of cell death induced by high-dose ascorbate. Instead, the cell death mechanism caused by high-dose ascorbate in glioblastoma cells shows evidence of ferroptosis. The results of the present work provide insights into the efficacy and mode of action of pharmacological ascorbate for the therapy of glioblastoma, as well as indications for possible approaches to increase the effectiveness of ascorbate treatment.

Overview

  • The study investigates the effects of high-dose ascorbate and dehydroascorbic acid on human glioblastoma cell lines and evaluates different treatment conditions for the combined administration of ascorbate with magnesium (Mg) and iron (Fe).
  • The study aims to determine the cytotoxicity and antiproliferative efficacy of high-dose ascorbate in human glioblastoma cells and investigate the mechanisms underlying cell death induced by ascorbate treatment.

Comparative Analysis & Findings

  • High-dose ascorbate showed significant cytotoxicity and antiproliferative efficacy in human glioblastoma cells, while dehydroascorbic acid had weaker effects. The reduction in cell viability and ascorbate-induced generation of intracellular reactive oxygen species (ROS) could be significantly increased by pre-treatment with ferric iron. The cell death mechanism caused by high-dose ascorbate in glioblastoma cells shows evidence of ferroptosis, which is independent of caspase-3.

Implications and Future Directions

  • The study demonstrates the potential of pharmacological ascorbate for the therapy of glioblastoma and provides insights into the mechanisms underlying ascorbate-induced cell death. Further research is needed to investigate the effectiveness of combined ascorbate-Mg-Fe treatment and to identify potential therapeutic targets for the treatment of glioblastoma.
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