Cancer chemoprevention by the antioxidant tempol in Atm-deficient mice.
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.
Schubert
Ralf
R
Department of Pediatrics, The Comprehensive Cancer Center, UCSD School of Medicine, La Jolla, CA 92093-0627, USA.
Erker
Laura
L
Barlow
Carrolee
C
Yakushiji
Hiroyuki
H
Larson
Denise
D
Russo
Angelo
A
Mitchell
James B
JB
Wynshaw-Boris
Anthony
A
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001260:Ataxia Telangiectasia / Q000235:genetics*; D015153:Blotting, Western; D018890:Chemoprevention / Q000379:methods*; D003497:Cyclic N-Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D005562:Formazans; D008136:Longevity / Q000187:drug effects; D008223:Lymphoma / Q000517:prevention & control*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013113:Spin Labels; D013778:Tetrazolium Salts; D013953:Thymus Neoplasms / Q000517:prevention & control*; D015430:Weight Gain / Q000187:drug effects
D000975:Antioxidants; D003497:Cyclic N-Oxides; D005562:Formazans; D017382:Reactive Oxygen Species; D013113:Spin Labels; D013778:Tetrazolium Salts; C079782:MTT formazan; C001803:tempol