过氧化物酶体增殖物激活受体γ激动剂治疗促肾上腺皮质激素型垂体腺瘤的实验研究  

Anticancer effects and mechanism of peroxisome proliferator activated receptorγ agonist in ACTH-secreting pituitary adenoma in vitro and in vivo

作　　者：李勇[1] 孙帅奇[2] 李普阳[2] 王文波[2] 阳永东[2] 夏学巍[2] 

机构地区：[1]桂林医学院研究生学院,广西541004 [2]桂林医学院附属医院神经外科

出　　处：《中华脑科疾病与康复杂志（电子版）》2013年第1期15-19,共5页Chinese Journal of Brain Diseases and Rehabilitation（Electronic Edition）

基　　金：广西自然科学基金项目(桂科自0991260);广西科技厅自筹经费项目(桂科自0899003);桂林医学院人才引进项目(06YJRCKT-38)

摘　　要：目的研究过氧化物酶体增殖物激活受体(peroxisome proliferators activated receptor,PPAR)γ激动剂对促肾上腺皮质激素(adrenocorticotropic hormone,ACTH)分泌型垂体腺瘤细胞生长的影响,并探讨相关机制。方法在体外实验中应用PPARγ激动剂罗格列酮作用分泌ACTH的垂体ATt20细胞,用四甲基偶氮唑盐微量酶反应比色法及PI染色分析ATt20细胞的增殖情况,Annexin V、PI双标法检测ATt20细胞的凋亡,并通过透射电镜予以形态学验证。在体内实验中,应用罗格列酮口服给药治疗ATt20裸小鼠载瘤动物模型6周,定期测量肿瘤体积和小鼠血浆ACTH激素水平。结果在体外细胞实验中,应用PPARγ激动剂后ATt20细胞出现增殖抑制,G0～G1期占85%±4%,高于对照组的71%±5%,差异有统计学意义(t=2.877,P<0.05);Annexin V、PI双标法凋亡检测并经电镜证实ATt20垂体腺瘤细胞在PPARγ激动剂作用后出现凋亡。动物实验结果显示经罗格列酮口服给药治疗后,治疗组和对照组的载瘤小鼠模型肿瘤体积分别为(751.72±80.48)mm3和(1058.82±173.33)mm3,血浆ACTH水平分别为(219.30±127.58)pg/ml和(2099.63±484.36)pg/ml,差异有统计学意义(t=3.795,P<0.05;t=15.266,P<0.01)。结论 PPARγ激动剂罗格列酮对ATt20细胞的增殖有抑制作用,并可以诱导其凋亡;在体内实验中罗格列酮可降低实验动物的血浆中ACTH水平,提示PPARγ激动剂有可能为药物治疗ACTH型垂体腺瘤提供一个新的有效途径。Objective To study the antitumor effect and mechanism of PPARγ agonists on adrenocorticotropie hormone secreting pituitary adenoma. Methods After treatment of PPARγ agonist, Rosiglitazone, cell proliferation detection of ATt20 cells was performed using MTlV and PI staining method. ATt20 ceils apoptosis detection was processing via Annexin V and PI apoptosis assay and transmission electron microscopy. In vivo, 10 BALB/c nude mice were implanted ATt20 cells subcutaneously; they were randomly divided into drug treatment group and control group when the implantation tumors were visible. Rosiglitazone was administered by oral gavage at 120 mg/kg per day for 6 weeks, while the mice in control group were treated with vehicle in the same way. Tumor volume and plasma ACTH level were measured in 3 days and 2 weeks interval, respectively. Results Rosiglitazone inhibited growth of ATt20 ceils in vitro, the proliferation cycle of ATt20 cell with treatment arrested in GO-G1 phase （85% ＋ 4% vs. 71% ＋ 5%, t = 2. 877 ,P 〈0. 05 ）, and the morphological apoptotic features of ATt20 cells were observed by transmission electron microscopy. In animal experiment, after treatment with rosiglitazone for six weeks, tumor volume of treatment group showed statistic difference（ t = 3. 795, P 〈 0.05 ） in comparison to control group, （751.72± 80. 48 ）mm3 vs. （1058. 82±173.33 ）mm3. Plasma ACTH levels of treatment and control group were （219. 30± 127. 58 ） pg/ml and （2099. 63 ±484. 36 ） pgcZml, respectively, the difference was significant （ t = 15. 266, P 〈 0. 01）. Conclusions Our finding indicated that the PPARγ agonist rosiglitazone showed antitumor effect on ATt20 cell line in vivo and in vitro, suggested that Rosiglitazone could be a new therapeutic medication of ACTH pituitary adenomas.

关 键 词：氧化物酶体增殖物激活受体 促肾上腺皮质激素 分泌ACTH的脑垂体腺瘤 凋亡 

分 类 号：R736.4[医药卫生—肿瘤]