Impact des ligands de PPARs, et leurs dérivés, sur les cellules cancéreuses coliques humaines : modifications des statuts redox et glycolytique

Abstract : Peroxisome Proliferator-activated Receptors (PPAR) are members of the nuclear receptor family. Pioglitazone and Fenofibrate belong respectively to the thiazolidinedione and fibrate family. Pioglitazone is an agonist of PPAR[gamma] isotype whereas Fenofibrate is an agonist of PPAR[alpha] isotype. Cancer cell exposure to each ligand inhibits cell growth and triggers apoptosis cell death. However, the effects of respective PPAR ligand on cell survival were found to be independent of receptor activation and were associated to redox changes within the cells. In order to discriminate PPAR independent from PPAR dependent activation, an analogue of Pioglitazone, [delta]-Pioglitazone was synthesized. The molecule binds to PPAR[gamma] without activating it. Two cancer cell lines established from human colon adenocarcinoma, HT29 and HCT116 were tested. Cell exposure to each molecule inhibited cell growth but cells did not undergo apoptosis cell death. Cell treatment induced the production of reactive species and the decrease of intracellular glutathione content. Pioglitazone or [delta]-Pioglitazone-mediated oxidative stress triggered the activation of the Nrf2/Keap1 pathway as assessed by the increases of Nrf2 target genes expression such as HO-1 and NQO1. In contrast, Fenofibrate treatment increased reactive species production but did no activate this pathway. Moreover, cell exposure to Pioglitazone, [delta]-Pioglitazone or Fenofibrate modulated cell metabolism, notably by enhancing glycolysis. In parallel, impact of 4-thiazolidinone derivatives synthesized in the laboratory was tested. These molecules are analogues of thiazolidinedione. Effect of 4-thiazolidinone treatments was assessed to cell growth arrest and redox changes within the HT29 cells. Several molecules have anti-proliferative effect and are able to generate oxidative stress without Nrf2/Keap1 pathway activation
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Sophie Huber-Villaume. Impact des ligands de PPARs, et leurs dérivés, sur les cellules cancéreuses coliques humaines : modifications des statuts redox et glycolytique. Médecine humaine et pathologie. Université de Lorraine, 2014. Français. ⟨NNT : 2014LORR0217⟩. ⟨tel-01751199⟩

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