Cancer chemoprevention by the antioxidant tempol in Atm-deficient mice

Ralf Schubert, Laura Erker, Carrolee Barlow, Hiroyuki Yakushiji, Denise Larson, Angelo Russo, James B. Mitchell, Anthony Wynshaw-Boris

Research output: Contribution to journalArticle

119 Scopus citations

Abstract

Reactive oxygen species (ROS) are important endogenous etiological agents for DNA damage, and ROS perform critical signaling functions in apoptosis, stress responses and proliferation. The correlation between a lower incidence of cancer in people who consume a diet high in naturally occurring antioxidants and the observed increased ROS in cancerous tissues suggest that antioxidants may be used in cancer chemoprevention. We tested this hypothesis by determining whether the well-described nitroxide antioxidant, tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), acts as a chemopreventative agent in Atm mutant mice, a model of the human cancer prone syndrome ataxia-telangiectasia. Tempol administered continuously via the diet after weaning resulted in an increased lifespan of these mice by prolonging the latency to thymic lymphomas. Tempol treatment reduced ROS, restored mitochondrial membrane potential, reduced tissue oxidative damage and oxidative stress, consistent with antioxidant effects. In addition, this nitroxide lowered weight gain of tumor prone mice without changes in food intake, metabolism or activity level and exhibited an anti-proliferative effect in vitro. Thus, tempol acts as a novel chemopreventative agent in this mouse model of a human cancer prone syndrome, associated with broad antioxidant effects.

Original languageEnglish (US)
Pages (from-to)1793-1802
Number of pages10
JournalHuman molecular genetics
Volume13
Issue number16
DOIs
StatePublished - Aug 15 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Schubert, R., Erker, L., Barlow, C., Yakushiji, H., Larson, D., Russo, A., Mitchell, J. B., & Wynshaw-Boris, A. (2004). Cancer chemoprevention by the antioxidant tempol in Atm-deficient mice. Human molecular genetics, 13(16), 1793-1802. https://doi.org/10.1093/hmg/ddh189