Cancer cells (relative to normal cells) demonstrate increased rates of glycolysis and pentose cycle activity and slightly decreased rates of respiration but the significance of this is unclear. Recent studies show that glucose de privation preferentially induces cytotoxicity and oxidative stress in cancer cells [Spitz et al., 2000]. Mitochondria have been hypothesized to be the site of prooxidant production during glucose deprivation. If this were true, then defects in cancer cell mitochondrial electron transport chain proteins could be causing altered sensitivity to glucose deprivation-induced cytotoxicity and these defects could be exploited for designing more efficacious combined modality cancer therapies. This proposal tests the hypothesis that mitochondria defects in mammalian cells contributes to increased formation of reactive oxygen species (ROS; i.e., superoxide and hydrogen peroxide) and this mediates increased susceptibility of human cancer cells to glucose deprivation-induced oxidative stress, relative to normal cells, using intact cells as well as isolated mitochondria from cells subjected to molecular manipulations of mitochondrial Complex II subunits.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA110611-03
Application #
7065271
Study Section
Special Emphasis Panel (ZRG1-F09 (20))
Program Officer
Lohrey, Nancy
Project Start
2004-06-01
Project End
2007-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$50,428
Indirect Cost
Name
University of Iowa
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Hadzic, Tanja; Aykin-Burns, Nükhet; Zhu, Yueming et al. (2010) Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress. Free Radic Biol Med 48:1024-33
Aykin-Burns, Nùkhet; Ahmad, Iman M; Zhu, Yueming et al. (2009) Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation. Biochem J 418:29-37
Dayal, Disha; Martin, Sean M; Owens, Kjerstin M et al. (2009) Mitochondrial complex II dysfunction can contribute significantly to genomic instability after exposure to ionizing radiation. Radiat Res 172:737-45
Jacobs, Kristi Muldoon; Pennington, J Daniel; Bisht, Kheem S et al. (2008) SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expression. Int J Biol Sci 4:291-9
Ahmad, Iman M; Abdalla, Maher Y; Aykin-Burns, Nukhet et al. (2008) 2-Deoxyglucose combined with wild-type p53 overexpression enhances cytotoxicity in human prostate cancer cells via oxidative stress. Free Radic Biol Med 44:826-34
Slane, Benjamin G; Aykin-Burns, Nukhet; Smith, Brian J et al. (2006) Mutation of succinate dehydrogenase subunit C results in increased O2.-, oxidative stress, and genomic instability. Cancer Res 66:7615-20
Andringa, Kelly K; Coleman, Mitchell C; Aykin-Burns, Nukhet et al. (2006) Inhibition of glutamate cysteine ligase activity sensitizes human breast cancer cells to the toxicity of 2-deoxy-D-glucose. Cancer Res 66:1605-10