Molecular Mechanisms of Anti-Tumor Effect of Peptide Analogs and Their Direct Effect on the Ovary

1)GnRH I拮抗剂Cetrorelx通过GnRH I受体介导的多种机制直接抑制人子宫内膜癌细胞株HEC-1A的增殖，参与细胞周期进程的多个事件，包括G2期细胞周期停滞、P53激活和cdc2失活，可能是由于上调Weel2。2)鉴于GnRH II对子宫内膜异位间质细胞(ESC)的抗增殖和抗炎作用，GnRH II在子宫内膜异位症患者在位和异位内膜中的低表达表明，内源性GnRH II介导的细胞抑制作用可能在子宫内膜异位症的发生发展中受到损害。3)西曲列酮直接抑制大鼠成熟颗粒细胞的增殖，其机制涉及细胞周期进程中的多个事件，包括G2期细胞周期停滞和细胞周期蛋白B1-cdc2复合体水平的下调，推测可能与p53水平上调和细胞凋亡有关。4)Fas/Fas配体系统通过激活caspase介导的级联通路，结合iNOS的表达，参与诱导大鼠颗粒细胞凋亡。NO通过抑制caspase的激活而抑制Fas/Fas配体系统诱导的细胞凋亡，提示Fas/Fas配体系统诱导的细胞凋亡通路与NO介导的抗凋亡通路在卵泡闭锁中存在交互作用。

1) GnRH I antagonist, Cetrorelix, directly inhibits the proliferation of HEC-1A human endometrial cancer cell line through mechanisms mediated by GnRH I receptor and involving multiple events in cell-cycle progression, including G2 phase cell cycle arrest coupled with the activation of p53 and the inactivation of cdc2, presumably attributable to an up-regulation of Weel.2) In light of the anti-proliferative and anti-inflammatory effects of GnRH II on endometriotic stromal cells (ESC), the lower expression of GnRH II in eutopic and ectopic endometrium of women with endometriosis suggests that endogenous GnRH II-mediated cytostatic regulation may be impaired in the development of endometriosis.3) Cetrorelix directly inhibits the proliferation of rat mature granulosa cells through mechanisms involving multiple events in cell cycle progression, including G2 phase cell cycle arrest coupled with down-regulation of cyclin B1-cdc2 complex levels, presumably attributable to an up-regulation of p53 levels and apoptosis.4) Fas/Fas ligand system is involved in inducing apoptosis through activation of a caspase-mediated cascade in rat granulosa cells, which is coupled with a decrease in iNOS expression. NO inhibits Fas/Fas ligand system-induced apoptosis by suppressing activation of the caspases, pointing to a cross-talk between Fas/Fas ligand system-induced apoptosis pathway and NO-mediated anti-apoptotic pathway in ovarian follicle atresia.