title: 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: BACKGROUND
  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
  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 2'-deoxyuridine 5'-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 5'-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.
authors.affiliation: Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe 650-0017, Japan.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ohara
authors.forename: Jiayin
authors.initials: J
authors.lastname: Wang
authors.forename: Qin
authors.initials: Q
authors.lastname: Xu
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.forename: Akira
authors.initials: A
authors.lastname: Morikawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Sasaki
authors.forename: Shigeki
authors.initials: S
authors.lastname: Yoshida
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Demanno
authors.forename: Kristof
authors.initials: K
authors.lastname: Chwalisz
authors.forename: Takeshi
authors.initials: T
authors.lastname: Maruo
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004963:Estrenes / Q000494:pharmacology*; D005260:Female; D019254:Genes, bcl-2 / Q000235:genetics; D006801:Humans; D020287:In Situ Nick-End Labeling; D007889:Leiomyoma / Q000473:pathology*; D009215:Myometrium / Q000473:pathology*; D010091:Oximes / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects*; D014594:Uterine Neoplasms / Q000473:pathology*
chemical_list: D004963:Estrenes; D010091:Oximes; D018809:Proliferating Cell Nuclear Antigen; D011980:Receptors, Progesterone; C488516:asoprisnil; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases