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Métabolisme énergétique et thérapie anticancéreuse : caractérisation des effets de dérivés désoufrés de la troglitazone sur les cellules d’adénocarcinomes mammaires

Abstract : Numerous therapeutic options are available for Luminal, HER2-enriched and Normal-like breast cancers. However, only chemotherapy can be used for triple-negative breast cancers. Moreover, regardless of breast cancer subtypes, there are many cases of absence of responsiveness and treatment resistances. In some cases, resistance comes from the presence of cancer stem cells (CSC) within the tumor. A possible therapeutic approach consists of targeting the energy metabolism often modified in cancer cells and CSC. Thiazolidinediones (TZD) are studied in this context since they display an anticancer activity and can induce alterations of the energy metabolism. Our laboratory studies troglitazone (TGZ) from which we could obtain several derivatives displaying a higher efficiency and a lower toxicity towards human hepatocytes. Desulfurylated derivatives of TGZ have been synthetized recently. First we performed a structure-activity relationship study in order to determine the impact of the sulfur atom on the anticancer activity. We observed that desulfurylated derivatives of TGZ displayed a higher efficiency towards breast cancer cells. and the most active compound was EP13, one of the desulfurylated TDZ derivatives, on breast cancer cells. The most active compound, EP13, combined different potentiating chemical modifications and the removal of the sulfur moiety from the TZD cycle. Unlike TGZ, EP13 induces apoptosis of MDA-MB-231 cells. Then we showed that EP13 disrupted energy metabolism of MDA-MB-231 cells by inducing alteration of mitochondrial respiratory chain function, associated with reactive oxygen species (ROS) production in MDA-MB-231 cells. A glycolysis stimulation seems to compensate secondarily the mitochondrial respiration alteration. EP13 at low doses was able to potentiate doxorubicin and 5-fluorouracil actions on MDA-MB-231 cells. Finally, we established a 3D cell culture model, which could allow enrichment in CSC. EP13 could alter the establishment of mammospheres from MDA-MB-231 and MCF-7 cells. This work suggests a potential interest of EP13 for the development of therapeutic strategies targeting energy metabolism. It remains to establish if there is a link between modifications of energy metabolism and EP13-induced apoptosis and to use the mammosphere experimental model to determine if EP13 can affect breast CSC.
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Claire Muller. Métabolisme énergétique et thérapie anticancéreuse : caractérisation des effets de dérivés désoufrés de la troglitazone sur les cellules d’adénocarcinomes mammaires. Endocrinologie et métabolisme. Université de Lorraine, 2019. Français. ⟨NNT : 2019LORR0305⟩. ⟨tel-02860580⟩

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