Triple-negative breast cancer is a highly aggressive type of breast tumors characterized by the lack of targets for hormone and anti-HER2 therapy. Inhibition of tumor metabolism is one of the promising approaches in the treatment of triple-negative breast cancer. As shown by previous studies, single treatments with oxidative phosphorylation (OxPhos) or glycolysis inhibitors were ineffective. The work aimed to develop novel oligomycin derivatives (OxPhos inhibitors) and evaluate their activity in combination with glycolysis inhibitors, 2-deoxyglucose (2DOG) and 3-bromopyruvate (3BP).
MCF-7 and MDA-MB-231 breast cancer cell lines and MCF-10A human mammary epithelial cells were obtained from the ATCC collection. Antiproliferative activity was measured by the MTT test. Immunoblotting was used for the assessment of signaling proteins.
New derivatives of oligomycin A have been obtained using Diels-Alder reactions. Using a screening, a lead derivative of oligomycin A, LCTA-3056, was selected, which is characterized by high selectivity for triple-negative breast cancer cells. Low toxicity of LCTA-3056 was revealed for MCF-10A human mammary epithelial cells. The high activity of combinations of LCTA-3056 with metabolic inhibitors, 3BP and 2DOG, against MDA-MB-231 triple-negative cancer cells was shown. Moreover, the combination of LCTA-3056 with 3BP modulated AMPK/mTOR/S6K pathway and effectively reversed the aggressive EMT phenotype of triple-negative breast cancer cells.
Combinatorial approach with oligomycin A derivatives may hold promise in the development of therapies against triple-negative breast cancers, including those with acquired resistance to standard chemotherapy. The research was supported by the Russian Foundation for Basic Research (# 18-015-00422, experiments with 2DOG) and Russian Science Foundation (#19-15-00245, experiments with MCF-7 cells).
The authors.
The Russian Foundation for Basic Research (# 18-015-00422, experiments with 2DOG) and Russian Science Foundation (#19-15-00245, experiments with MCF-7 cells).
All authors have declared no conflicts of interest.