A comparative analysis of inhibitors of the glycolysis pathway in breast and ovarian cancer cell line models
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Chrysi Xintaropoulou1, Carol Ward1, Alan Wise2, Hugh Marston2,4, Arran Turnbull3, Simon P. Langdon1
1Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK
2IOMET Pharma, Nine, Edinburgh BioQuarter, Edinburgh, EH16 4UX, UK
3Breakthrough Breast Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK
4Current Address: Eli Lilly Research and Development, Windlesham, Surrey, GU20 6PH, UK
Simon P. Langdon, e-mail: Simon.Langdon@ed.ac.uk
Keywords: glycolysis, inhibitors, ovarian cancer, breast cancer
Received: May 12, 2015 Accepted: June 29, 2015 Published: July 16, 2015
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.
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