Delta-2-Troglitazone targets mitochondria in triple-negative breast cancer cells: a metabolic change contributing to sensitization of cancer cells to chemotherapy?

Background: Resistance to conventional therapies for triple-negative mammary tumors are strong arguments for the search for new therapeutic agents. A strategy is to develop drugs targeting energetic metabolism to sensitize cancer cells to chemotherapy. Thiazolidinediones display antiproliferative effects which could be the result of mechanisms altering cell metabolism. Our objectives are to characterize the modifications of the triple-negative breast cancer cell line MDA-MB231 metabolism after Delta-2-Troglitazone (D2T) exposure and to define whether D2T could potentiate the action of chemotherapeutic agents. Methods: Cell numbers were assessed by crystal violet staining. NAD+ and NADH concentrations were determined by chemiluminescence. Lactate and glucose concentrations were measured with an YSI 2950 Biochemistry Analyzer. Mitochondrial activity was assessed by oxygraphy. Results: 48h cell treatment with D2T (75 µM) inhibited cell proliferation. At the metabolic level, NAD+/NADH ratio was increased after a 24h treatment, suggesting that glycolysis and/or mitochondrial respiration could be altered. Oxygen consumption was diminished after a 24h exposure to D2T, associated with a decreased mitochondrial efficiency and a mitochondrial decoupling. At the glycolytic level, lactate production and glucose consumption were increased in D2T-treated cells. Finally, D2T at a lower dose (15 µM) potentiated the effects of 2-DG (2-Deoxyglucose, a glycolytic inhibitor) and doxorubicin on cell viability. Conclusion: D2T induces metabolic changes in cancer cells MDA-MB231. D2T targets mitochondrial activity likely leading to the stimulation of glycolysis. Besides, a low dose of D2T potentiates the action of 2-DG and doxorubicin on cell viability. The impact of the D2T/doxorubicin combination on proliferation and apoptosis has to be characterized. Overall, the link between the metabolic alteration observed with D2T and its antiproliferative effect has to be demonstrated.