A Novel Selective Progesterone Receptor Modulator Asoprisnil (J867) Inhibits Proliferation and Induces Apoptosis in Cultured Human Uterine Leiomyoma Cells in the Absence of Comparable Effects on Myometrial Cells

Abstract

Context: Asoprisnil, a selective progesterone (P4) receptor (PR) modulator (SPRM) with mixed P4 agonist/antagonist activities, reduces uterine leiomyoma volume in a dose-dependent manner in the presence of follicular phase estrogen concentrations. The evidence from clinical studies suggests that asoprisnil may directly target the uterine leiomyomata. Objective and Methods:The present study evaluated the effects of asoprisnil on cell proliferation, the expression of apoptosis-related proteins, and apoptosis in cultured human uterine leiomyoma cells and matched normal myometrial cells. PR-A and PR-B expression in the two types of cells was comparatively evaluated. Cell proliferation, proliferating cell nuclear antigen (PCNA)-positive rate, and TUNEL-positive rate were assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, immunocytochemistry, and terminal deoxynucleotidyl transferase-mediated 2Ј-deoxyuridine 5Ј-triphosphate nick end labeling (TUNEL) assay, respectively. The expression of apoptosis-related proteins and PR was assessed by Western blot analysis. Results:Compared with untreated cultures, asoprisnil decreased the number of viable cultured cells, the PCNA-positive rate, and PCNA protein expression in cultured leiomyoma cells. Asoprisnil increased the TUNEL-positive rate, cleaved caspase-3, and cleaved poly(adenosine 5Ј-diphosphate-ribose) polymerase expression and decreased Bcl-2 protein expression in cultured leiomyoma cells. These effects were dose and time dependent. In cultured myometrial cells, however, asoprisnil did not affect cell proliferation and apoptosis. PR-B expression was elevated in cultured leiomyoma cells compared with cultured myometrial cells, whereas no differences in PR-A expression were noted between the two cell types. Conclusions:These results show that asoprisnil inhibits proliferation and induces apoptosis in cultured uterine leiomyoma cells in the absence of comparable effects on cultured normal myometrial cells, suggesting a cell type-specific effect.

Medical Management of leipmyomas-emphasis for different geographical regions

“…Further studies have demonstrated that asoprisnil reduces volume of uterine fibroids in a dose dependent manner [30] . Similarly in vitro studies have shown Asoprisnil (As) inhibits proliferation and induces apoptosis in cultured human uterine leiomyoma cells in absence of similar effect in myome-trial cells [34] . Just like in nonhuman primates Asoprisnil (As) was associated with decrease in proliferation markers Ki 67 while PTEN (Phosphatase and tensin homologue) a tumour suppressor gene expression remained unaltered ,in patients receiving 10/25 mg asoprisnil, thus making it a safe option [31] .…”

Recent advances in structure of progestins and their binding to progesterone receptors

“…In this case, the PR ligand complex presents only one different conformation as compared to that of 12. This fact could explain why 10 was more effective than 12 or 13 by considering the presence of co-activators 35,36 . On the bases of their effect as pure antagonist, different types of PR antagonists were identified and described; this prevents the binding of PR complex to DNA (13, Figure 4) [32][33][34] .…”

“…On the bases of their effect as pure antagonist, different types of PR antagonists were identified and described; this prevents the binding of PR complex to DNA (13, Figure 4) [32][33][34] . Partial antagonists are those which facilitate the binding of the ligandjoin PR to the progesterone response element (PRE) present in DNA helix; however, they show also an agonistic activity in the target tissues (12, 11, Figure 3) 35 . The antiproliferative activity of steroid 10 ( Figure 4) is explained on the ground that this steroid can attach to the ligand binding domain of PR, a helix 12 conformation.…”

Medical Management of Uterine Fibroids

“…It induces amenorrhea and reduces uterine fibroid volume in a dose-dependent manner [54,55], and it reduces uterine artery blood flow [56]. Asoprisnil has marginal abortifacient activity and no antiglucocorticoid effect [57][58][59][60]. This drug does not induce estrogen deprivation symptoms or breakthrough bleeding.…”