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Nitroxides as antioxidants: Tempol protects against E09 cytotoxicity

  • Chapter
Oxygen/Nitrogen Radicals: Cell Injury and Disease

Part of the book series: Developments in Molecular and Cellular Biochemistry ((DMCB,volume 37))

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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)

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Authors and Affiliations

  1. Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA

    Ayelet M. Samuni, William DeGraff, Murali C. Krishna & James B. Mitchell

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  1. Ayelet M. Samuni
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  2. William DeGraff
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  3. Murali C. Krishna
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  4. James B. Mitchell
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Editors and Affiliations

  1. Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road Mall Stop B167, Morgantown, WV, 26505, USA

    Val Vallyathan , Xianglin Shi Ph.D.  & Vince Castranova ,  & 

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Samuni, A.M., DeGraff, W., Krishna, M.C., Mitchell, J.B. (2002). Nitroxides as antioxidants: Tempol protects against E09 cytotoxicity. In: Vallyathan, V., Shi, X., Castranova, V. (eds) Oxygen/Nitrogen Radicals: Cell Injury and Disease. Developments in Molecular and Cellular Biochemistry, vol 37. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1087-1_37

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  • DOI: https://doi.org/10.1007/978-1-4615-1087-1_37

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5388-1

  • Online ISBN: 978-1-4615-1087-1

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