Since the 1920's it has been observed that cancer cells (relative to normal cells) demonstrate increased rates of glycolysis and pentose cycle activity as well as slightly decreased rates of respiration but the significance of this to cancer therapy is unclear. Recent studies have shown that glucose deprivation preferentially induces cytotoxicity and oxidative stress in human cancer cells, relative to normal cells [Appendix 1]. Mitochondria have been hypothesized to be the site of prooxidant production during glucose deprivation. If this were generally true, glucose deprivation-induced oxidative stress could represent a defect in tumor cell mitochondrial metabolism amenable to manipulations designed to improve cancer therapy. The current proposal will test the hypothesis that mitochondrial production of reactive oxygen species (ROS; i.e., superoxide and hydrogen peroxide) mediates the increased susceptibility of human cancer cells to glucose deprivation-induced metabolic oxidative stress, relative to normal cells.
Specific Aim 1 will determine using electron transport chain blockers (i.e., antimycin A, myxothiazol, and rotenone), if intact human cancer cells (or isolated mitochondria) demonstrate alterations in ROS production by mitochondrial electron transport chain Complexes I, II, and/or III that contribute to increased susceptibility to glucose deprivation-induced oxidative stress, relative to normal cells.
Specific Aim 2 will determine if rho(0) cancer cells, deficient in functional mitochondrial electron transport chains demonstrate altered susceptibility to glucose deprivation-induced cytotoxicity and oxidative stress, relative to parental rho(+) cells containing fully functional electron transport chains.
Specific Aim 3 will determine using adenoviral vectors as well as stably transfected cell lines, if over expession of antioxidant enzymes that scavenge superoxide and hydrogen peroxide (i.e., catalase, superoxide dismutases) are capable of altering the biological effects of glucose deprivation in cancer cells.
Specific Aim 4 will determine if 2-deoxy-d-glucose is capable of mimicking the effects of glucose deprivation seen in Aims 1-3. The long-term goal is to provide a rigorous mechanistic understanding of the differential susceptibility of cancer cells to glucose deprivation-induced oxidative stress for the purpose of developing combined modality cancer therapy based on differences between oxygen metabolism in normal vs. cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100045-03
Application #
7006057
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Poland, Alan P
Project Start
2004-04-07
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
3
Fiscal Year
2006
Total Cost
$295,269
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
Li, Ling; Fath, Melissa A; Scarbrough, Peter M et al. (2015) Combined inhibition of glycolysis, the pentose cycle, and thioredoxin metabolism selectively increases cytotoxicity and oxidative stress in human breast and prostate cancer. Redox Biol 4:127-35
Moussa, Marwan; Goldberg, S Nahum; Kumar, Gaurav et al. (2014) Radiofrequency ablation-induced upregulation of hypoxia-inducible factor-1? can be suppressed with adjuvant bortezomib or liposomal chemotherapy. J Vasc Interv Radiol 25:1972-82
Moussa, Marwan; Goldberg, S Nahum; Kumar, Gaurav et al. (2014) Nanodrug-enhanced radiofrequency tumor ablation: effect of micellar or liposomal carrier on drug delivery and treatment efficacy. PLoS One 9:e102727
Moussa, Marwan; Goldberg, S Nahum; Tasawwar, Beenish et al. (2013) Adjuvant liposomal doxorubicin markedly affects radiofrequency ablation-induced effects on periablational microvasculature. J Vasc Interv Radiol 24:1021-33
Scarbrough, Peter M; Mapuskar, Kranti A; Mattson, David M et al. (2012) Simultaneous inhibition of glutathione- and thioredoxin-dependent metabolism is necessary to potentiate 17AAG-induced cancer cell killing via oxidative stress. Free Radic Biol Med 52:436-43
Kim, Seog-Young; Rhee, Juong G; Song, Xinxin et al. (2012) Breast cancer stem cell-like cells are more sensitive to ionizing radiation than non-stem cells: role of ATM. PLoS One 7:e50423
Owens, Kjerstin M; Aykin-Burns, N?khet; Dayal, Disha et al. (2012) Genomic instability induced by mutant succinate dehydrogenase subunit D (SDHD) is mediated by O2(-•) and H2O2. Free Radic Biol Med 52:160-6
Ahmed, Muneeb; Moussa, Marwan; Goldberg, S Nahum (2012) Synergy in cancer treatment between liposomal chemotherapeutics and thermal ablation. Chem Phys Lipids 165:424-37
Yang, Wei; Ahmed, Muneeb; Tasawwar, Beenish et al. (2012) Combination radiofrequency (RF) ablation and IV liposomal heat shock protein suppression: reduced tumor growth and increased animal endpoint survival in a small animal tumor model. J Control Release 160:239-44
Goldberg, S Nahum (2012) Science to practice: What do molecular biologic studies in rodent models add to our understanding of interventional oncologic procedures including percutaneous ablation by using glyceraldehyde-3-phosphate dehydrogenase antagonists? Radiology 262:737-9

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