PPAR-gamma receptor ligands: novel therapy for pituitary adenomas.
Pituitary tumors cause considerable morbidity due to local invasion, hypopituitarism, or hormone hypersecretion. In many cases, no suitable drug therapies are available, and surgical excision is currently the only effective treatment. We show here abundant expression of nuclear hormone receptor PPAR-gamma in all of 39 human pituitary tumors. PPAR-gamma activating thiazolidinediones (TZDs) rosiglitazone and troglitazone induced G(0)-G(1) cell-cycle arrest and apoptosis in human, rat somatolactotroph, and murine gonadotroph pituitary tumor cells, and suppressed in vitro hormone secretion. In vivo development and growth of murine somatolactotroph and gonadotroph tumors, generated by subcutaneous injection of prolactin-secreting (PRL-secreting) and growth hormone-secreting (GH-secreting) GH3 cells, luteinizing hormone-secreting (LH-secreting) LbetaT2 cells, and alpha-T3 cells, was markedly suppressed in rosiglitazone-treated mice, and serum GH, PRL, and LH levels were attenuated in all treated animals (P < 0.009). These results demonstrate that PPAR-gamma is an important molecular target in pituitary adenoma cells and PPAR-gamma ligands inhibit tumor cell growth and GH, PRL, and LH secretion in vitro and in vivo. TZDs are proposed as novel oral medications for managing pituitary tumors.
Cedars-Sinai Research Institute, University of California Los Angeles School of Medicine, Los Angeles, California 90048, USA. HeaneyA@csmc.edu
Anthony P
AP
Heaney
Manory
M
Fernando
Shlomo
S
Melmed
D000236:Adenoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000502:physiology; D002469:Cell Separation; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011897:Random Allocation; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013844:Thiazoles / Q000627:therapeutic use*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D008024:Ligands; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C089946:2,4-thiazolidinedione