Abstract 19P
Background
Cancer cell metabolism has been proposed as a new strategy to fight cancer. Elevated aerobic glycolysis of cancer cells for energy production provides a possibility for therapeutic intervention. 2-deoxy-D-glucose (2DG) and metformin (MET) have been used in combination to inhibit glycolysis and induce cell death in various tumour types. The required doses have exceeded that achievable in human plasma. Deep eutectic solvents (DES) are mixtures of solid compounds that form liquids due to a large depression of the melting point and possess unique properties such as pharmacological activity. DESs have been reported to demonstrate anticancer properties but have not previously been studied in vivo mouse models.
Methods
We investigated the preclinical efficacy of targeting the tumour bioenergetic pathway using conventional and DES mixtures of MET and 2DG in MDA-MB-231 (human breast adenocarcinoma) and UFH-001 (triple-negative breast cancer) cells. We evaluated the in vitro anti-tumour activity of the individual components MET and 2DG and the DES mixture for comparison. In addition, we examined in vivo efficacy using xenograft mouse models.
Results
2DG and MET alone were not sufficient to promote tumour cell death, reflecting the limited efficacy demonstrated in clinical trials. A combined use of 2DG and MET also failed to induce cell death. However, the DES mixture of 2DG and MET led to significant cell death associated with decrease in cellular ATP and sustained autophagy. DES mixtures had the highest impact on tumour cell viability, exceeding the effect of 2DG/MET as single agents or combinations at all clinically relevant concentrations.
Conclusions
We developed a DES mixture from 2DG/MET, which significantly induced apoptosis of cancer cells, exceeding the effect of single components or conventional mixtures. Deprivation of tumour bioenergetics by dual inhibition of energy pathways might be an effective novel therapeutic approach for human breast cancer tumours. The DES does not necessitate the use of toxic components or additional solvents and could be used to develop clinical applications for targeting breast cancer cell metabolism.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Chembrain LTD research organization.
Funding
Chembrain LTD research institution.
Disclosure
S. Vuoti: Full/Part-time employment, currently works at Sanofi Genzyme, however, the presented research is not related to Sanofi but was conducted in 2017-2018 before joining Sanofi: Sanofi Genzyme. All other authors have declared no conflicts of interest.