Dramatic extension of tumor latency and correction of neurobehavioral phenotype in Atm-mutant mice with a nitroxide antioxidant.
Mutations in the ATM gene (mutated in ataxia telangiectasia) in both humans and mice predispose to lymphoid tumors. A defect in this gene also causes neurodegeneration in humans and a less severe neurological phenotype in mice. There is some evidence that oxidative stress contributes to these defects, suggesting that antioxidants could alleviate the phenotype. We demonstrate here that the antioxidant 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) dramatically delays the onset of thymic lymphomas in Atm(-/-) mice which is not due to an enhancement of apoptosis by CTMIO. We also show that this compound corrects neurobehavioral deficits in these mice and reduces oxidative damage to Purkinje cells. The likely mechanism of action of CTMIO is due to a reduction in oxidative stress, which is protective against both the tumor progression and the development of neurological abnormalities. These data suggest that antioxidant therapy has considerable potential in the management of ataxia telangiectasia and possibly other neurodegenerative disorders where oxidative stress is implicated.
Gueven
Nuri
N
Queensland Institute of Medical Research, Brisbane, Qld, Australia.
Luff
John
J
Peng
Cheng
C
Hosokawa
Kazuyuki
K
Bottle
Steven E
SE
Lavin
Martin F
MF
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D001522:Behavior, Animal / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008223:Lymphoma / Q000235:genetics* / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*
C480578:5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl; D000975:Antioxidants; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007211:Indoles; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases