Pharmacological Inhibition of Tumor Metabolism As Anticancer Treatment

Increased glycolytic metabolism is a hallmark characteristic of cancer cells, a phenomenon known as the “Warburg effect”. This involves increased glucose consumption and lactate secretion by cancer cells. Drug treatments that reverse this metabolic shift have the potential to achieve selective inhibition of cancer cell growth. We are testing the ability of multiple metabolic inhibitors to selectively inhibit the in vitro growth of B-cell lymphoma by reversing the Warburg effect. These inhibitors target several distinct metabolic nodes. For example, 2-deoxyglucose inhibits glucose phosphorylation by hexokinase, dichloroacetate stimulates glucose oxidation by mitochondria, and oxamate inhibits glucose conversion to lactate. The P493-6 B-cell line is used in this work, which expresses the Myc oncogene from a tunable promoter and allows us to achieve High, Low, or No Myc expression.  This enables us to assess the effects of inhibitors while varying the tumorigenicity of our cell model.  An IC50 growth inhibition curve was constructed for each inhibitor under normoxic and hypoxic conditions to determine the appropriate dose for metabolic analysis. Future work will include analysis of the effect of simultaneous inhibition using a combination of inhibitors.