Combination therapy targeting cancer metabolism

Abstract

Cancer cells undergo significant metabolic adaptation. Cellular transformation enhances both glycolysis and mitochondrial respiration efficiency through the induction of HIF-1α and HIF-2α. In this process, energy production and synthesis of macromolecules are maximized with minimal ROS accumulation. Furthermore, a series of antioxidant enzymes are induced to mitigate the damaging effects of ROS. Examination of these metabolic changes provides rationale for a synergistic approach to combination anti-cancer therapy; targeted inhibition of HIF and inhibition of cellular defenses against oxidative stress.

Figure 1

Diagrams showing: A, metabolism of glucose in cancer cells with the induction of both glycolysis and efficient mitochondrial respiration. Glucose is transported into the cell and is metabolized to pyruvate. In aerobic respiration, pyruvate enters the mitochondria, where it is converted to acetyl-CoA. Acetyl-CoA combines with oxaloacetate to form citrate and is then catabolized through the TCA cycle. Electrons are donated, through NADH and FADH₂, to the electron transport chain. Electron transfer is coupled to the translocation of protons (H+) from the mitochondrial matrix to the intermembrane space to generate a proton gradient. Oxygen (O₂) is the final electron acceptor at complex IV, and in this process is reduced to water (H₂O). The final step of oxidative phosphorylation involves F₁F₀ATP synthase whereby protons flow down the electrochemical gradient to generate ATP from ADP. Early transfer of electrons to oxygen at complexes I and III results in the generation of ROS. B, effect of inhibiting HIF-1α and HIF-2α. C, effect of inhibiting HIF-1α and HIF-2α and inhibiting cellular antioxidant defenses.