PPAR-γ receptor ligands:: novel therapy for pituitary adenomas
PPAR-γ receptor ligands:: novel therapy for pituitary adenomas
复制标题
DOI：
10.1172/jci200316575
复制
发表时间：
2003-05-01
影响因子：
15.9
通讯作者：
Melmed, S
中科院分区：
文献类型：
--
作者：
Heaney, AP;Fernando, M;Melmed, S
垂体瘤由于局部侵袭、垂体功能减退或激素分泌过多而导致相当高的发病率。在许多情况下，没有合适的药物治疗，手术切除是目前唯一有效的治疗方法。我们在这里显示丰富的核激素受体PPAR-gamma在所有39人垂体瘤的表达。PPAR-gamma激活噻唑烷二酮类（TZDs）罗格列酮和曲格列酮诱导人、大鼠促体细胞乳细胞和小鼠促性腺激素垂体瘤细胞的G（0）-G（1）细胞周期阻滞和凋亡，并抑制体外激素分泌。皮下注射催乳素分泌物产生的小鼠体乳细胞和促性腺细胞肿瘤的体内发育和生长（PRL分泌）和生长激素分泌（GH分泌）GH 3细胞，黄体化细胞分泌（LH分泌）L β T2细胞和α-T3细胞在罗格列酮处理的小鼠中受到明显抑制，血清GH、PRL、LH水平均降低（P < 0.009）。这些结果表明，PPAR-gamma是垂体腺瘤细胞中的重要分子靶标，PPAR-gamma配体在体外和体内抑制肿瘤细胞生长和GH、PRL和LH分泌。TZD被提议作为治疗垂体瘤的新型口服药物。
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 somatolactorroph 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.