Evaluation of ∆2-pioglitazone, an analogue of pioglitazone, on colon cancer cell survival: Evidence of drug treatment association with autophagy and activation of the Nrf2/Keap1 pathway

Huber,Sophie; Valente,Sergio; Chaimbault,Patrick; Schohn,Hervé

doi:10.3892/ijo.2014.2408

Evaluation of ∆2-pioglitazone, an analogue of pioglitazone, on colon cancer cell survival: Evidence of drug treatment association with autophagy and activation of the Nrf2/Keap1 pathway

Authors:
- Sophie Huber
- Sergio Valente
- Patrick Chaimbault
- Hervé Schohn
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Affiliations: University of Lorraine, CNRS Unit 7565 - SRSMC Campus Bridoux, F-57070 Metz, France, University of Lorraine, EA 4632 - Laboratory of Chemistry and Physics - A2MC, F-57078 Metz Cedex 3, France
Published online on: April 29, 2014 https://doi.org/10.3892/ijo.2014.2408
Pages: 426-438

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Abstract

Thiazolidinediones have been shown to exhibit anti-proliferative effects against cancer cells derived from diverse tissue origins both in vivo and in vitro. We studied the anti-proliferative impact of 5-{4-(2-(5-ethyl-pyridin-2-yl)-ethoxy)-benzylidene}-thiazolidine-2,4-dione (∆2-pioglitazone), an analogue of pioglitazone, which binds to the nuclear peroxisome proliferator activated receptor-γ without activating it, on human adenocarcinoma-derived HT29 and HCT116 cells. In HTC116 cells, exposure to ∆2-pioglitazone reduced cell growth, but HT29 cells reached the plateau phase of growth after three days. ∆2-pioglitazone treatment did not trigger cells to enter apoptosis but enhanced the autophagy process. The effect of ∆2-pioglitazone treatment was related to the increase of oxygen and nitric oxide-derived species production and decreased glutathione content. Moreover, pre-treatment with an antioxidant before addition of ∆2-pioglitazone limited cell growth inhibition, reduced the production of reactive species and attenuated autophagy within the cells. The impact of the drug was associated with activation of the Nrf2/Keap1 pathway as demonstrated by the increased protein content of several antioxidant enzymes, notably heme-oxygenase-1.

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