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The chemistry and tumoricidal activity of nitric oxide/hydrogen peroxide and the implications to cell

R Farias-Eisner1, G Chaudhuri, E Aeberhard

  • 1Department of Obstetrics-Gynecology, University of California at Los Angeles School of Medicine, 90095-1735, USA.

The Journal of Biological Chemistry
|March 15, 1996
PubMed

Insights

Nitric oxide (NO) and hydrogen peroxide (H2O2) cause ovarian cancer cell death. Superoxide and peroxynitrite are not directly involved, suggesting a metal-catalyzed oxidant mechanism contributes to NO-induced cytotoxicity.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Cancer Research

Background:

  • Nitric oxide (NO) donors are investigated for cancer therapy.
  • Understanding NO's cytotoxic mechanisms is crucial for drug development.
  • Ovarian cancer cell lines provide a model for studying cancer cytotoxicity.

Purpose of the Study:

  • To elucidate the mechanism of 3-morpholino-sydnonimine-induced cytotoxicity in human ovarian cancer cells.
  • To determine the roles of nitric oxide (NO), hydrogen peroxide (H2O2), superoxide (O2), and peroxynitrite in NO-mediated cell death.
  • To investigate the impact of NO on cellular hydrogen peroxide degradation pathways and its implications for cytotoxicity.

Main Methods:

  • Exposure of OVCAR cells to the NO donor 3-morpholino-sydnonimine.
  • Measurement of cell viability and reactive oxygen species (ROS) production.
  • Enzyme activity assays for catalase and glutathione peroxidase (GSHPx)-glutathione reductase system.
  • Assessment of cellular responses to ebselen and selenium depletion.

Main Results:

  • NO-mediated cytotoxicity was dependent on both NO and H2O2, but not directly on superoxide or peroxynitrite.
  • A potent oxidant, potentially metal-catalyzed, is implicated in NO/H2O2 toxicity.
  • NO inhibited catalase activity but not the GSHPx-glutathione reductase system.
  • Ebselen conferred protection, while selenium depletion increased susceptibility to NO toxicity.

Conclusions:

  • NO and H2O2 act synergistically to induce ovarian cancer cell death via a novel oxidative mechanism.
  • Cellular defense systems, particularly the GSHPx-glutathione reductase pathway, play a significant role in modulating sensitivity to NO-induced cytotoxicity.
  • Targeting these pathways could offer strategies to enhance the efficacy of NO-based cancer therapies.

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