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-di one (Delta 2-pioglitazone), an analogue of pioglitazone, which binds to the nuclear peroxisome proliferator activated receptor-gamma without activating it, on human adenocarcinoma-derived HT29 and HCT116 cells. In HTC116 cells, exposure to Delta 2-pioglitazone reduced cell growth, but HT29 cells reached the plateau phase of growth after three days. Delta 2-pioglitazone treatment did not trigger cells to enter apoptosis but enhanced the autophagy process. The effect of Delta 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 Delta 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/Keapl pathway as demonstrated by the increased protein content of several antioxidant enzymes, notably heme-oxygenase-1.