title: A comparative analysis of inhibitors of the glycolysis pathway in breast and ovarian cancer cell line models.
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.
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
authors.forename: Chrysi
authors.initials: C
authors.lastname: Xintaropoulou
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
authors.forename: Carol
authors.initials: C
authors.lastname: Ward
authors.affiliation: IOMET Pharma, Nine, Edinburgh BioQuarter, Edinburgh, EH16 4UX, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Wise
authors.affiliation: IOMET Pharma, Nine, Edinburgh BioQuarter, Edinburgh, EH16 4UX, UK.|Current Address: Eli Lilly Research and Development, Windlesham, Surrey, GU20 6PH, UK.
authors.forename: Hugh
authors.initials: H
authors.lastname: Marston
authors.affiliation: Breakthrough Breast Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
authors.forename: Arran
authors.initials: A
authors.lastname: Turnbull
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Langdon
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D019344:Lactic Acid / Q000378:metabolism; D061986:MCF-7 Cells; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019344:Lactic Acid; D005947:Glucose; D010100:Oxygen
keywords: breast cancer; glycolysis; inhibitors; ovarian cancer