A new derivative of troglitazone affects energy metabolism of triple negative breast cancer cells: potential interest for anticancer treatment - Archive ouverte HAL Accéder directement au contenu
Communication Dans Un Congrès Année : 2018

A new derivative of troglitazone affects energy metabolism of triple negative breast cancer cells: potential interest for anticancer treatment

Résumé

Background: Triple - negative breast tumours, characterized by the absence of estrogen, progesterone and HER 2 receptors expression, are difficult to treat . Indeed, there is no targeted therapy for these tumours. Moreover, their response rate to conventional therapies is low, they often develop resistances and the recurrence rate is high. Energy metabolism is often modified in cancer cells and this is an interesting target to develop new therapeutic strategies. In this context, we are developing original derivatives of troglitazone , a thiazolidinedione that exhibits anticancer activity and metabolic effects . The objective of the present study was to characterize the effects of EP 13, a desulfured troglitazone derivative, on the triple - negative breast cancer cell line MDA - MB - 231. Methods : The triple - negative breast cancer cell line MDA - MB 231 was exposed to EP 13 for different time periods. Cell number was assessed by crystal violet staining assay. Apoptosis and cellular DNA content were detected by flow cytometry using annexin V - FITC and PI staining, respectively. NAD+ (nicotinamide adenine dinucleotide) and NADH concentrations were determined by chemiluminescence (Promega kit). Lactate and glucose concentrations in cell culture medium were measured with an YSI 2950 Biochemistry Analyzer. Oxygen consumption rate was measured by seahorse XF Analyzer. Changes in mitochondrial membrane potential were detected by flow cytometry using the JC - 1 probe (BDTM MitoScreen kit). Results: After 48 hours of treatment, EP 13 affected MDA - MB - 231 cells survival, with an IC 50 value of 5 . 9 μM . Moreover, it triggered cell apoptosis after 48 and 72 hours. At the metabolic level, EP 13 induced a decrease in the NAD+/NADH ratio suggesting a metabolic reprograming. The cells displayed a lower oxygen consumption rate and loss of mitochondrial membrane potential from 6 h of exposure to EP 13. Preliminary results suggested that Reactive Oxygen Species were not involved in the action of EP 13 since N - acetyl cysteine (NAC) did not modify the cell population in the sub - G 1 compartment of the cell cycle. Moreover, EP 13 treated cells displayed a higher glycolytic rate, revealed by higher lactate production and glucose consumption. The combination of EP 13 with a glycolysis inhibitor, 2 - deoxy - D - glucose (2 - DG, a glucose analogue) or oxamate (pyruvate analogue and LDH - A inhibitor) exhibited a synergistic effect on the decrease of MDA - MB - 231 cell number. Conclusion: These findings indicated that EP 13 (IC 50 = 5.9 ± 0.1 μM) was much more potent than troglitazone (IC 50 = 46.0 ± 4.5 μM). This compound induced metabolic changes in triple - negative breast cancer cells. The high glycolytic activity was likely a compensatory mechanism of mitochondria alteration. The targets of EP 13 and the link between metabolic reprograming and EP 13 induced apoptosis have now to be determined.
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Dates et versions

hal-01937228 , version 1 (28-11-2018)

Identifiants

  • HAL Id : hal-01937228 , version 1

Citer

Claire Muller, Stéphanie Grandemange, Jerome Kluza, Frédéric Bost, Eline Piquard, et al.. A new derivative of troglitazone affects energy metabolism of triple negative breast cancer cells: potential interest for anticancer treatment. 11ème Forum du Cancéropôle Est, Nov 2018, Reims, France. ⟨hal-01937228⟩
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