Discussion

Many cancers, unlike normal tissue, rely on glycolysis rather than mitochondrial oxidative phosphorylation for the production of energy, even in the presence of oxygen. This is known as the Warburg effect. This alternative metabolic route could represent a potential strategy to preferentially kill cancer cells. This study set out to determine the role of aerobic glycolysis in two female cancers, using breast and ovarian cancer cell line models, with the ultimate objective of identifying a translatable target for the development of novel cancer drug therapies. Nine compounds that have been reported to inhibit key enzymes of the glycolysis pathway were selected; among them more established inhibitors such as Phloretin, 3-Bromopyruvate, Dichloroacetate and Oxamic acid as well as four more novel inhibitors STF31, WZB117, 3PO- [3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one] and NHI1. These were compared against a panel of 4 breast cancer and 4 ovarian cancer cell lines. The effects of the compounds on cell proliferation, glucose uptake and lactate production were investigated. Each compound tested blocked glycolysis as indicated by glucose accumulation in the culture media combined with a decrease in the production of lactate, the final product of glycolysis. Targeting the glycolytic pathway at different stages inhibited cell proliferation in a concentration-dependent manner. Proliferative growth of both breast and ovarian cancer cell lines appeared dependent on all the targets examined. Furthermore, the effect of oxygen level on sensitivity to glycolysis inhibition was investigated by examining the sensitivity to the inhibitors under a range of O2 levels (21%- 7%- 2%- 0.5% O2). Consistent with the Warburg effect, cancer cells demonstrated increased sensitivity to glycolysis inhibition under normoxic conditions. In conclusion, breast and ovarian cancer cells proved dependent on aerobic glycolysis, and this pathway provides a target for cancer treatment.

Authors: Chrysi Xintaropoulou 1, Carol Ward 1, Alan Wise 2, Hugh Marston 2#, Simon Langdon 1
1 Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU
2 TPP Global Development, Nine, Edinburgh BioQuarter, Little France Road, Edinburgh, EH16 4UX;
# current address: Eli Lilly Research and Development, Sunninghill Road, Windlesham, Surrey, GU20 6PH