Douglas Spitz- Professor

 

 

 

 

 

 

Research Interests

   For 80 years it has been noted that cancer cells exhibit increased glycolysis and pentose phosphate cycle activity, while demonstrating only slightly reduced rates of respiration. These metabolic differences were thought to arise as a result of "damage" to the respiratory mechanism and tumor cells were thought to compensate for this defect by increasing glycolysis (Science 132:309).
            Recently, glucose deprivation-induced oxidative stress has been shown to cause cytotoxicity, activation of signal transduction (i.e., ERK1, ERK2, JNK, and Lyn kinase), and increased expression of genes associated with malignancy (i.e., bFGF and c-Myc) in MCF-7/ADR human breast cancer cells (J. Biol. Chem. 273:5294; Free Radic. Biol. Med. 26:419). These results have lead to the proposal that intracellular oxidation/reduction reactions involving hydroperoxides and thiols may provide a mechanistic link between metabolism, signal transduction, and gene expression in these human tumor cells (Ann. NY Acad. Sci. 899:349).
            Further studies have shown that several other transformed human cell types appear to be more susceptible to glucose deprivation-induced cytotoxicity and oxidative stress than untransformed human cell types. In SV40 transformed human fibroblasts glucose deprivation-induced cytotoxicity is dependent upon O2 concentration.
            Finally, studies with mitochondrial electron transport chain blockers that increase superoxide and hydrogen peroxide production have shown that glucose deprivation-induced oxidative stress can be greatly enhanced in transformed cells vs. normal cells. These results support the working hypothesis that transformed cells (cancer cells) may have a defective mitochondrial respiratory chain leading to increased steady state levels of reactive oxygen species and glucose metabolism may be increased to provide reducing equivalents to compensate for this defect.
           This theorectical construct is utilized in basic science study of tumor vs. normal cell mitochondria metabolism to determine the role that damage to genes coding for mitochondrial electron transport chain proteins may play in cancer and aging.
           The laboratory is also using these principals in preclinical translational studies to develop strategies for imaging glucose utilization and alterations in mitochondrial metabolism in cancer cells for the purpose of predicting which patients may respond to therapies base on taking advantage of fundamental defects in oxidative metabolism. This work is also being used to develop novel strategies for treating tumors with combined therapies utilizing inhibitors of glucose and hydroperoxide metabolism together with agents that increase respiratory dependent damage caused by reactive oxygen species.

Example Publications

• Spitz DR, Sim JE, Ridnour LA, Galoforo SS, and Lee YJ: Glucose deprivation-induced oxidative stress in human tumor cells: a fundamental defect in metabolism? Ann. NY Acad. Sci. 2000; 899:349-362. [Publication]
• Spitz DR, Azzam EI, Li JJ, and Gius D: Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: a unifying concept in stress response biology. Cancer and Metastasis Reviews 2004; 23:311–322.[Publication]
• Ahmad IM, Aykin-Burns N, Sim JE, Walsh SA, Higashikubo R, Buettner GR, Venkataraman S, Mackey MA, Flanagan S, Oberley LW, and Spitz DR: Mitochondrial O2•- and H2O2 mediate glucose deprivation-induced cytotoxicity and oxidative stress in human cancer cells. J. Biol. Chem. 2005; 280(6):4254-4263.[Publication]
• Slane BG, Aykin-Burns N, Smith BJ, Kalen AL, Goswami PC, Domann FE, and Spitz DR: Mutation of succinate dehydrogenase subunit C (SDHC) results in increased O2•-, oxidative stress, and genomic instability. Cancer Res. 2006; 66(15): 7615-7620.[Publication]
• Simons AL, Ahmad IM, Mattson DM, Dornfeld KJ, and Spitz DR: 2-Deoxy-D-glucose (2DG) combined with cisplatin enhances cytotoxicity via metabolic oxidative stress in human head and neck cancer cells. Cancer Res. 2007; 67(7): 3364–70.[Publication]
• Simons AL, Fath MA, Mattson DM, Smith BJ, Walsh SA, Graham MM, Hichwa RD, Buatti JM, Dornfeld KJ, and Spitz DR: Enhanced response of human head and neck cancer xenograft tumors to Cisplatin combined with 2-deoxy-D-glucose correlates with increased 18F-FDG uptake as determined by PET imaging. Int J. Radiat. Oncol. Biol. & Phys. 2007; 69(4):1222-30.[Publication]

See attached PDF files for the papers listed above.

Honors, Awards and Organizations

• 1987 Young Investigator Travel Award - Radiation Research Society
• 1990 Young Investigator Award - International Society for Free Radical Research/The Oxygen Society.
• 2001 Editorial Board - Free Radical Biology and Medicine
• 2005 Leader - Free Radical Cancer Biology Program, Holden Comprehensive Cancer Center, The University of Iowa
• 2005 Director of Radiation and Free Radical Research Core Laboratory, Holden Comprehensive Cancer Center, The University of Iowa
• 2006 Member NCI/NIH Radiation Therapeutics and Biology Study Section
• 2008 Director Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa

Education

• PhD, 1984, Radiation Biology, Minor-Biochemistry, University of Iowa, Iowa City, Iowa

• B.A., Biology/Sociology, 1978, Grinnell College, Grinnell, Iowa