Delta-2-troglitazone sensitizez triple-negative breast cancer cells to chemotherapy: a consequence of mitochondrial dysfunction?
Résumé
Background: Thiazolidinediones display antiproliferative effects which could 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: 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: 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 or one of its derivatives, associated with a decreased mitochondrial efficiency and a mitochondrial decoupling. At the glycolytic level, lactate production and glucose consumption were increased. Finally, low doses of D2T potentiated the effects of 2-Deoxyglucose and doxorubicin on cell viability.
Conclusion: D2T derivatives target mitochondria likely leading to the stimulation of glycolysis. A low dose of D2T potentiates the action of 2-Deoxyglucose 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 mitochondrial dysfunction observed with D2T and its antiproliferative effect has to be demonstrated.