Differential effects of PPARgamma agonists on the metabolic properties of gliomas and astrocytes.
Recent studies show that thiazolinediones (TZDs), agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma), induce apoptosis in glioma and glioblastoma cells. Here we compared the effects of troglitazone (Trog), a TZD with low affinity for binding to PPARgamma but with potent metabolic effects, on survival and metabolism in GL261 glioma cells versus primary astrocytes. Trog dose-dependently induced cell death in GL261 cells (with over 90% death at 30 microM) but did not cause any toxicity in astrocytes at the same doses. Measurements of glucose and lactate levels after incubation with Trog (30 microM) indicated an overall increase of glucose consumption and lactate production in both cell types. In astrocytes the ratio of lactate produced to glucose utilized was not significantly altered by Trog, while in glioma cells this ratio was decreased by about 40%. Trog dose-dependently reduced mitochondrial membrane potential (DeltaPsi(m)) in both cell types; and the loss of DeltaPsi(m) was greater in the tumor cells (90% loss at 20 microM) than in astrocytes (70% loss at 20 microM). These results suggest that differences in metabolic responses could contribute to the selective resistance of astrocytes to cytotoxic effects of Trog. TZDs such as Trog should therefore be considered for testing in treatment of gliomas.
Spagnolo
Alessandra
A
Department of Anesthesiology, University of Illinois, 835 South Wolcott, Chicago, IL 60612, USA. aspagnol@uic.edu
Grant
Erica N
EN
Glick
Roberta
R
Lichtor
Terry
T
Feinstein
Douglas L
DL
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002839:Chromans / Q000627:therapeutic use / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D005947:Glucose / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D045162:Thiazolidinediones / Q000627:therapeutic use / Q000633:toxicity*; D000077288:Troglitazone
D000970:Antineoplastic Agents; D002839:Chromans; D047495:PPAR gamma; D045162:Thiazolidinediones; D019344:Lactic Acid; D000077288:Troglitazone; D005947:Glucose