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Human Molecular Genetics Advance Access originally published online on June 22, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 16 1793-1802
DOI: 10.1093/hmg/ddh189
Human Molecular Genetics, Vol. 13, No. 16 © Oxford University Press 2004; all rights reserved

Cancer chemoprevention by the antioxidant tempol in Atm-deficient mice

Ralf Schubert1,2,3,{dagger}, Laura Erker1,2,3,{dagger}, Carrolee Barlow4,{ddagger}, Hiroyuki Yakushiji1,2,3,¶, Denise Larson4, Angelo Russo5, James B. Mitchell5 and Anthony Wynshaw-Boris1,2,3,4,*

1Department of Pediatrics, 2Department of Medicine and 3The Comprehensive Cancer Center, UCSD School of Medicine, La Jolla, CA, USA, 4Genetic Disease Research Branch, NHGRI and 5Radiation Biology Branch, NCI, Bethesda, MD, USA

Received April 28, 2004; Accepted June 11, 2004

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.

* To whom correspondence should be addressed at: School of Medicine, University of California, San Diego, 9500 Gilman Drive, Mail Stop 0627, La Jolla, CA, 92093-0627, USA. Tel: +1 8588223400; Fax: +1 8588223409; Email: awynshawboris{at}ucsd.edu


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