Docosahexaenoic Acid Enhances 2-deoxyglucose Treatment and Antagonizes Metformin Treatment in the Reduction of Intracellular ATP in Breast Cancer

Abstract

Epidemiological studies have shown that diets rich in omega-3 polyunsaturated fatty acids (PUFAs) correlate with lower incidence of cancer. Docosahexaenoic acid (DHA), an omega-3 PUFA was shown to suppress a wide range of cancer subtypes by inhibiting adenosine triphosphate (ATP), which thereby induces metabolic stress within the cell. By deregulating the cellular energetics of cancer cells, DHA has been shown to express tumor-suppressing effects. Other clinically relevant drugs that have proven effectiveness in targeting cancer metabolism include Metformin and 2-deoxyglucose (2DG). While both display their tumor-suppressing effects by reducing intracellular ATP, they do so by different mechanisms. Metformin targets the electron transport chain, while 2DG inhibits glycolysis. This study investigated the combinatorial effects of DHA with Metformin, as well as with 2DG. DHA was shown to enhance the effects of 2DG, but it displayed antagonistic behavior when treated in tandem with Metformin. Although DHA, Metformin, and 2DG each display similar results in ATP inhibition when treated alone, these results suggest that DHA’s ability to enhance the efficacy of other drugs is dependent on factors that may be related to pathway, mechanism, or localization.