Abstract
Many cancer cells rely on aerobic glycolysis for energy production and targeting of this pathway is a potential strategy to inhibit cancer cell growth. In this study, inhibition of five glycolysis pathway molecules (GLUT1, HKII, PFKFB3, PDHK1 and LDH) using 9 inhibitors (Phloretin, Quercetin, STF31, WZB117, 3PO, 3-bromopyruvate, Dichloroacetate, Oxamic acid, NHI-1) was investigated in panels of breast and ovarian cancer cell line models. All compounds tested blocked glycolysis as indicated by increased extracellular glucose and decreased lactate production and also increased apoptosis. Sensitivity to several inhibitors correlated with the proliferation rate of the cell lines. Seven compounds had IC50 values that were associated with each other consistent with a shared mechanism of action. A synergistic interaction was revealed between STF31 and Oxamic acid when combined with the antidiabetic drug metformin. Sensitivity to glycolysis inhibition was also examined under a range of O2 levels (21% O2, 7% O2, 2% O2 and 0.5% O2) and greater resistance to the inhibitors was found at low oxygen conditions (7% O2, 2% O2 and 0.5% O2) relative to 21% O2 conditions. These results indicate growth of breast and ovarian cancer cell lines is dependent on all the targets examined in the glycolytic pathway with increased sensitivity to the inhibitors under normoxic conditions.
Highlights
In the 1920s, Otto Warburg demonstrated that cancer cells exhibit an alteration in their metabolism when compared with non-malignant cells
Targeted inhibition of the glycolysis pathway in breast and ovarian cancer cell lines The effect of inhibitors targeted against upstream components of the glycolysis pathway (GLUT1, hexokinase II, PFKFB3) and the downstream component lactate dehydrogenase (LDH)-A were compared on cell proliferation
For Phloretin, the IC50 values ranged between 36–135 μM while IC50 values ranged between 44–106 μM for Quercetin
Summary
In the 1920s, Otto Warburg demonstrated that cancer cells exhibit an alteration in their metabolism when compared with non-malignant cells. Cancer cells frequently utilise glycolysis even in the presence of sufficient amounts of oxygen [1, 2]. This persistence of aerobic glycolysis in many cancers is well substantiated and considered a ‘hallmark’ of advanced cancers [3]. The fact that cancer cells reduce their dependence on mitochondrial oxidative phosphorylation and are more reliant on glycolysis provides a wide range of potential targets for therapy. Targeting aerobic glycolysis is a promising strategy to preferentially kill cancer cells which are dependent on this pathway and in recent years multiple glycolytic inhibitors have been developed [4,5,6]. To date only a few agents have been assessed within in vivo experiments and even fewer have undergone clinical trials [4,5,6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
