Pioglitazone modulates tumor cell metabolism and proliferation in multicellular tumor spheroids.
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.
Gottfried
Eva
E
Department of Hematology and Internal Oncology, University Medical School, Franz-Josef Strauss Allee 11, 93042 Regensburg, Germany. eva.gottfried@klinik.uni-regensburg.de
Rogenhofer
Sebastian
S
Waibel
Heidi
H
Kunz-Schughart
Leoni A
LA
Reichle
Albrecht
A
Wehrstein
Monika
M
Peuker
Alice
A
Peter
Katrin
K
Hartmannsgruber
Gabi
G
Andreesen
Reinhard
R
Kreutz
Marina
M
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
D002839:Chromans; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D019344:Lactic Acid; D003847:Deoxyglucose; D000077288:Troglitazone; C039671:ciglitazone; D000077205:Pioglitazone