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

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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.