The Role of Akt Pathway Signaling in Glucose Metabolism and Metabolic Oxidative Stress

D.R. Spitz et al. (eds.), Oxidative Stress in Cancer Biology and Therapy, Oxidative Stress in Applied Basic Research and Clinical Practice, DOI 10.1007/978-1-61779-397-4_2, © Springer Science+Business Media, LLC 2012 Abstract Glucose metabolism plays an important role in hydroperoxide detoxifi cation and the inhibition of glucose metabolism has been shown to increase prooxidant production and cytotoxicity in cancer cells. Increased Akt pathway signaling has been shown to be directly correlated with increased rates of glucose metabolism observed in cancer cells versus normal cells. These observations have led to the proposal that inhibition of Akt signaling would inhibit glycolysis and increase hydroperoxide production which would preferentially kill tumor cells versus normal cells via oxidative stress. The current study shows that inhibition of the Akt pathway inhibits glucose consumption and induces parameters indicative of oxidative stress such as glutathione disulfi de (%GSSG) and thioredoxin reductase (TR) activity in human head and neck cancer (HNSCC) cells. A theoretical model to explain the results is presented and implications for the use of Akt pathway inhibitors in combination with glycolytic inhibitors and/or manipulations that increase prooxidant production are discussed.