O 2⋅- and H 2 O 2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

Cancer Cell. 2017 Apr 10;31(4):487-500.e8. doi: 10.1016/j.ccell.2017.02.018. Epub 2017 Mar 30.

Abstract

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2⋅- and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

Keywords: ferritin; glioblastoma multiforme; hydrogen peroxide; labile iron metabolism; non-small cell lung cancer; oxidative stress; pharmacological ascorbate; superoxide; superoxide dismutase; transferrin receptor.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Ascorbic Acid / administration & dosage
  • Ascorbic Acid / adverse effects
  • Ascorbic Acid / pharmacology*
  • Brain Neoplasms / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / radiotherapy
  • Cell Line, Tumor
  • Chemoradiotherapy / methods
  • Female
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Iron / metabolism*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Lung Neoplasms / radiotherapy
  • Male
  • Mice, Nude
  • Oxygen / metabolism
  • Radiation-Sensitizing Agents / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Radiation-Sensitizing Agents
  • Hydrogen Peroxide
  • Iron
  • Ascorbic Acid
  • Oxygen