TY - JOUR
T1 - Effect of the reduction of superoxide dismutase 1 and 2 or treatment with α-tocopherol on tumorigenesis in Atm-deficient mice
AU - Erker, Laura
AU - Schubert, Ralf
AU - Elchuri, Sailaja
AU - Huang, Ting Ting
AU - Tarin, David
AU - Mueller, Klaus
AU - Zielen, Stefan
AU - Epstein, Charles J.
AU - Wynshaw-Boris, Anthony
N1 - Funding Information:
We are grateful to Don Cleveland for first suggesting this study in Atm-deficient mice. We also thank our animal technician Donna Holland for exemplary handling of our mice during the survival study and Jeff Long for assistance with the statistical analysis of the data in this paper. We are also grateful to Judy Nordberg at the San Diego VA Hospital FACS Core for help and advice with flow cytometry. This work was supported in part by grants from the National Institutes of Health: AG16633 (T.T.H.) and AG16998 (C.J.E.).
PY - 2006/8/15
Y1 - 2006/8/15
N2 - Atm-deficient mice, a cancer-prone model of the human disease ataxia-telangiectasia, display increased levels of oxidative stress and damage. Chronic treatment of these mice with the nitroxide antioxidant and superoxide dismutase (SOD) mimetic Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) resulted in an increased latency to tumorigenesis. We initially hypothesized that the chemopreventative effect of Tempol was due to its SOD mimetic activity reducing cellular oxidative stress and damage. However, it is also possible that the chemopreventative effect of Tempol results from mechanisms other than directly reducing superoxide radical-induced oxidative stress and damage. To help distinguish between these possibilities, we attempted to genetically increase oxidative stress in Atm-deficient mice by either removing cytosolic Sod1 or reducing mitochondrial Sod2, or we attempted to decrease oxidative stress by treatment of Atm-deficient mice with α-tocopherol. Surprisingly, we found that reducing both Atm and Sod1 or Atm and Sod2 did not shorten latency to tumorigenesis or significantly affect life span. Furthermore, continuous administration of α-tocopherol did not affect latency to thymic lymphomas. Thus, genetically reducing Sod in Atm-deficient mice or treatment with α-tocopherol had no effect on survival or tumorigenesis, suggesting that the chemopreventative effect of Tempol may be at least partially independent of its effects on reducing oxidative damage and stress.
AB - Atm-deficient mice, a cancer-prone model of the human disease ataxia-telangiectasia, display increased levels of oxidative stress and damage. Chronic treatment of these mice with the nitroxide antioxidant and superoxide dismutase (SOD) mimetic Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) resulted in an increased latency to tumorigenesis. We initially hypothesized that the chemopreventative effect of Tempol was due to its SOD mimetic activity reducing cellular oxidative stress and damage. However, it is also possible that the chemopreventative effect of Tempol results from mechanisms other than directly reducing superoxide radical-induced oxidative stress and damage. To help distinguish between these possibilities, we attempted to genetically increase oxidative stress in Atm-deficient mice by either removing cytosolic Sod1 or reducing mitochondrial Sod2, or we attempted to decrease oxidative stress by treatment of Atm-deficient mice with α-tocopherol. Surprisingly, we found that reducing both Atm and Sod1 or Atm and Sod2 did not shorten latency to tumorigenesis or significantly affect life span. Furthermore, continuous administration of α-tocopherol did not affect latency to thymic lymphomas. Thus, genetically reducing Sod in Atm-deficient mice or treatment with α-tocopherol had no effect on survival or tumorigenesis, suggesting that the chemopreventative effect of Tempol may be at least partially independent of its effects on reducing oxidative damage and stress.
KW - Antioxidants
KW - Ataxia-telangiectasia
KW - Mouse models
KW - Superoxide dismutase 1 and 2
KW - Tempol
KW - α-Tocopherol
UR - http://www.scopus.com/inward/record.url?scp=33746079988&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33746079988&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2006.04.032
DO - 10.1016/j.freeradbiomed.2006.04.032
M3 - Article
C2 - 16863992
AN - SCOPUS:33746079988
SN - 0891-5849
VL - 41
SP - 590
EP - 600
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 4
ER -