Abstract 14P
Background
Energy imbalance is one of the tumor cells' key properties in some cases supporting rapid progression and resistance to therapies. Simultaneous effects on glycolysis and other signaling pathways seem to be a promising strategy for anticancer therapy. Objectives: evaluation of the effects of glucose deprivation and glycolysis inhibitor (2-Deoxy-D-Glucose, 2DOG) on the antiproliferative activities of various anticancer agents, searching for promising combinations.
Methods
To simulate glucose deprivation DMEM medium with or without 1, 4.5 g / L glucose was used. Treatment with 2DOG was applied to inhibit glycolysis. Cell viability was estimated by MTT. The activity of the estrogen receptor alpha was assessed by gene reporter analysis. Immunoblotting was used to evaluate protein expression (AMPK, Akt).
Results
Under glucose deprivation, we showed that the effect of antiproliferative agents from various classes on MCF-7 cells almost does not change. No enhanced effect of edelfosin, tamoxifen, apigenin, genistein, doxorubicin, and 1-pentafluorophenylamido-5-sulfonamidoindane (CAIX inhibitor), everolimus, wortmannin was found. Glucose deprivation and 2DOG sensitized MCF-7 cells to two only drugs, metformin and oligomycin A. Glucose deprivation causes a 1000-fold increase in the antiproliferative effects of oligomycin A in hormone-dependent MCF-7 breast cancer cells. Moreover, glucose withdrawal leads to a significant compensatory activation of Akt, one of the main anti-apoptotic proteins, while oligomycin A further enhances Akt activity. AMPK, an energy cell sensor, is activated by 1 nM oligomycin A only under glucose starvation. Oligomycin A and metformin show more pronounced antiestrogenic effects during glucose deprivation.
Conclusions
Glucose starvation and pharmacological inhibition of glycolysis are of interest for harnessing the antitumor action of oligomycin A and metformin in ERα-positive breast cancer, including through improving their antiestrogenic potencies. This project was supported by the Russian Foundation for Basic Research (agreements 18-29-09017, studies of ERα signaling and 19-015-00058, studies of everolimus) and the Russian Science Foundation (agreement 20-13-00402, studies of CAIX inhibitor).
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Russian Foundation for Basic Research (agreements 18-29-09017, studies of ERα signaling and 19-015-00058, studies of everolimus) and the Russian Science Foundation (agreement 20-13-00402, studies of CAIX inhibitor).
Disclosure
All authors have declared no conflicts of interest.