Heaney Anthony P, Fernando Manory, Yong William H, Melmed Shlomo
Department of Medicine, Cedars-Sinai Research Institute, University of California Los Angeles School of Medicine, Los Angeles, California, USA.
Nat Med. 2002 Nov;8(11):1281-7. doi: 10.1038/nm784. Epub 2002 Oct 15.
Adrenocorticotrophic hormone (ACTH)-secreting pituitary tumors are associated with high morbidity due to excess glucocorticoid production. No suitable drug therapies are currently available, and surgical excision is not invariably curative. Here we demonstrate immunoreactive expression of the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) exclusively in normal ACTH-secreting human anterior pituitary cells: PPAR-gamma was abundantly expressed in all of six human ACTH-secreting pituitary tumors studied. PPAR-gamma activators induced G0/G1 cell-cycle arrest and apoptosis and suppressed ACTH secretion in human and murine corticotroph tumor cells. Development of murine corticotroph tumors, generated by subcutaneous injection of ACTH-secreting AtT20 cells, was prevented in four of five mice treated with the thiazolidinedione compound rosiglitazone, and ACTH and corticosterone secretion was suppressed in all treated mice. Based on these findings, thiazolidinediones may be an effective therapy for Cushing disease
促肾上腺皮质激素（ACTH）分泌性垂体瘤因糖皮质激素分泌过多而导致高发病率。目前尚无合适的药物治疗方法，手术切除也并非总能治愈。在此我们证明核激素受体过氧化物酶体增殖物激活受体γ（PPAR-γ）仅在正常分泌ACTH的人垂体前叶细胞中有免疫反应性表达：在所研究的6例人ACTH分泌性垂体瘤中，PPAR-γ均大量表达。PPAR-γ激活剂可诱导人及小鼠促肾上腺皮质激素瘤细胞发生G0/G1期细胞周期阻滞和凋亡，并抑制ACTH分泌。通过皮下注射分泌ACTH的AtT20细胞产生的小鼠促肾上腺皮质激素瘤，在用噻唑烷二酮类化合物罗格列酮治疗的5只小鼠中有4只得到预防，且所有治疗小鼠的ACTH和皮质酮分泌均受到抑制。基于这些发现，噻唑烷二酮类药物可能是治疗库欣病的有效疗法。
