title: Pioglitazone modulates tumor cell metabolism and proliferation in multicellular tumor spheroids.
abstract: The anti-diabetic thiazolidinedione compound pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, and selective cyclooxygenase-2 inhibitors are clinically used in patients with advanced malignancies. Several previously published in vivo and in vitro studies showed growth inhibitory effects on different cancer cell lines. However, the underlying mechanisms are fairly unclear. Here, we analyzed the effects of pioglitazone in combination with other drugs in a three-dimensional multicellular tumor spheroid culture system (MCTS) generated from the two prostate carcinoma cell lines PC3 and LNCaP. As expected, pioglitazone also inhibited tumor cell proliferation in the MCTS system. Further studies revealed that pioglitazone lowered the pH of the culture medium, decreased oxygen consumption and increased lactate secretion in both tumor cell lines. Other glitazones, troglitazone and ciglitazone, had similar effects. The combination of pioglitazone with 2-deoxyglucose, a potent inhibitor of glycolysis, had an additive effect on the inhibition of cell proliferation and led to MCTS disintegration. Our data propose a new mechanism of growth inhibition by pioglitazone through modulation of the tumor cell metabolism.
authors.affiliation: Department of Hematology and Internal Oncology, University Medical School, Franz-Josef Strauss Allee 11, 93042 Regensburg, Germany. eva.gottfried@klinik.uni-regensburg.de
authors.forename: Eva
authors.initials: E
authors.lastname: Gottfried
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rogenhofer
authors.forename: Heidi
authors.initials: H
authors.lastname: Waibel
authors.forename: Leoni A
authors.initials: LA
authors.lastname: Kunz-Schughart
authors.forename: Albrecht
authors.initials: A
authors.lastname: Reichle
authors.forename: Monika
authors.initials: M
authors.lastname: Wehrstein
authors.forename: Alice
authors.initials: A
authors.lastname: Peuker
authors.forename: Katrin
authors.initials: K
authors.lastname: Peter
authors.forename: Gabi
authors.initials: G
authors.lastname: Hartmannsgruber
authors.forename: Reinhard
authors.initials: R
authors.lastname: Andreesen
authors.forename: Marina
authors.initials: M
authors.lastname: Kreutz
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D047495:PPAR gamma / Q000819:agonists; D000077205:Pioglitazone; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018874:Spheroids, Cellular / Q000473:pathology; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
chemical_list: D002839:Chromans; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D019344:Lactic Acid; D003847:Deoxyglucose; D000077288:Troglitazone; C039671:ciglitazone; D000077205:Pioglitazone