Reactive oxygen species abrogate the anticarcinogenic effect of eicosapentaenoic acid in Atm-deficient mice.
Recent studies have demonstrated that n-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) are able to suppress cell proliferation and inhibit tumor growth. The objective of our study was to investigate the influence of a high dose EPA on the development of the tumor phenotype in ataxia-telangiectasia mutated (Atm)-deficient mice, a genetic cancer model that is associated with increased levels of oxidative stress. We analyzed toxicity, proliferation, cell-cycle progression, and apoptosis of EPA in vitro and latency to tumorigenesis in vivo. Because of the impact of reactive oxygen species (ROS) on the tumor incidence in ataxia telangiectasia (AT), we further analyzed the effect of EPA on the generation of ROS and oxidative DNA damage (ODD). EPA effectively inhibited proliferation, altered cell-cycle progression, and induced apoptosis of tumor cells (AT-4). EPA showed no effect on the latency to tumorigenesis in Atm-deficient mice. EPA treatment was accompanied by a significant increase of ROS and ODD. Our results demonstrate the antiproliferative effect of EPA on tumor cells by alteration of cell-cycle progression and induction of apoptosis in vitro. On the other hand, EPA treatment of Atm-deficient mice led to the formation of ROS and accumulation of ODD that might have abrogated the anticarcinogenic effect caused by EPA.
Schubert
Ralf
R
Children's Hospital I, Goethe-University, Frankfurt, Germany.
Reichenbach
Janine
J
Koch
Claudia
C
Kloess
Stephan
S
Koehl
Ulrike
U
Mueller
Klaus
K
Baer
Patrick
P
Beermann
Christopher
C
Boehles
Hansjosef
H
Zielen
Stefan
S
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000172:deficiency*; D015118:Eicosapentaenoic Acid / Q000032:analysis / Q000494:pharmacology*; D004910:Erythrocyte Membrane / Q000737:chemistry; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency*
D016588:Anticarcinogenic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D015118:Eicosapentaenoic Acid; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases