Biochemical correlates of thiazolidinedione-induced adipocyte differentiation by high-resolution magic angle spinning NMR spectroscopy.
Thiazolidinediones, a class of synthetic ligands to the peroxisome proliferator-activated receptor-gamma, induce terminal adipocyte differentiation of 3T3 F442A cells, and have already been used as alternative therapeutic agents for the treatment of liposarcoma in clinical trials. The biochemical changes occurring in the 3T3 F442A cell line and well-differentiated liposarcoma following induction of adipocyte differentiation with the thiazolidinedione troglitazone were measured using high-resolution magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy. 3T3 F442A cell differentiation was characterized by a large accumulation of intracellular triglyceride and withdrawal from the cell cycle. Phosphatidylcholine (PTC), phosphocholine (PC), myo-inositol, and glycerol were found to be possible biochemical markers for adipocyte differentiation induced by thiazolidenediones. The molar ratio of PTC to PC increased fourfold in differentiated 3T3 F442A cells compared to undifferentiated cells, suggesting a substantial increase in CTP:phosphocholine cytidylyltransferase activity with differentiation. A 2.8-fold increase in the PTC:PC ratio was observed in the lipoma-like well-differentiated liposarcoma of three patients who were treated with troglitazone when compared to liposarcoma from patients not treated with this drug. Thus, this ratio may be an NMR-detectable marker of troglitazone efficacy and response to differentiation therapy for liposarcoma.
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D002839:Chromans / Q000627:therapeutic use; D005434:Flow Cytometry; D006801:Humans; D008024:Ligands; D008080:Liposarcoma / Q000188:drug therapy / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D051379:Mice; D010713:Phosphatidylcholines / Q000378:metabolism; D010767:Phosphorylcholine / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism; D000077288:Troglitazone
D000970:Antineoplastic Agents; D002839:Chromans; D008024:Ligands; D010713:Phosphatidylcholines; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D010767:Phosphorylcholine; C089946:2,4-thiazolidinedione; D000077288:Troglitazone