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Nitroxides as antioxidants: Tempol protects against E09 cytotoxicity

  • Ayelet M. Samuni
  • William DeGraff
  • Murali C. Krishna
  • James B. Mitchell
Chapter
  • 408 Downloads
Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 37)

Abstract

Nitroxide free radicals have been shown to be potent antioxidants in a variety of experimental models using diverse means of insults. Among other insults, nitroxides have been shown effective in inhibiting cytotoxicity of quinone-based drugs such as streptonigrin and mitomycin C. These drugs and other chemotherapeutic agents have the potential to undergo bioreductive activation by the normal reducing enzymes within a cell. In the present work we studied the effect of the nitroxide Tempol on the cytotoxicity induced by EO9, a mitomycin C analogue, in HT29 cells under aerobic and hypoxic conditions. The study was aimed to better understand the mechanism of E09 cytotoxicity and the molecular level of the nitroxide’s mode of protection. The reactions of Tempol with activated EO9, and the reactive species formed during EO9 activation were studied in a cell-free solution, using spin-trapping, and electron paramagnetic resonance (EPR) spectrometry. Our results indicate that EO9 induced similar cytotoxicity in HT29 cells under aerobic and hypoxic conditions while Tempol provided similar and almost complete protection to both aerobic and hypoxic cells. The results indicate that E09 cytotoxicity is due to both 1- and 2-electron reductive activation processes, with aerobic toxicity caused by back-oxidation of the hydroquinone to the semiquinone, EO9’. Tempol serves both as a useful tool in the study of the mechanisms of quinone-mediated cytotoxicity and as a potent antioxidant against the damaging effects of redox cycling quinones and semiquinones by scavenging of E09’ or detoxification of and and Hp,. (Mol Cell Biochem 234/235: 327-333, 2002)

Key words:

EPR mitomycin C redox cycling quinone bioreductive 

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Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Ayelet M. Samuni
    • 1
  • William DeGraff
    • 1
  • Murali C. Krishna
    • 1
  • James B. Mitchell
    • 1
  1. 1.Radiation Biology Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaUSA

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