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.
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.
University of Lorraine, CNRS Unit 7565 - SRSMC Campus Bridoux, F-57070 Metz, France.
Sophie
S
Huber
University of Lorraine, CNRS Unit 7565 - SRSMC Campus Bridoux, F-57070 Metz, France.
Sergio
S
Valente
University of Lorraine, EA 4632 - Laboratory of Chemistry and Physics - A2MC, F-57078 Metz Cedex 3, France.
Patrick
P
Chaimbault
University of Lorraine, CNRS Unit 7565 - SRSMC Campus Bridoux, F-57070 Metz, France.
Hervé
H
Schohn
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D000077205:Pioglitazone; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*
C000594499:5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione; D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D045162:Thiazolidinediones; D000077205:Pioglitazone