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