The
progesterone receptor (PR) is a key regulator of female reproductive functions. Compounds with
progesterone inhibiting effects (PR antagonists) have found numerous utilities in female reproductive health, ranging from
contraception to potential treatment of
progesterone-dependent diseases like uterine
leiomyomas. Based on in vitro characteristics such as
DNA binding activity and partial agonistic transcriptional behavior in the presence of
protein kinase A activators (
cyclic-AMP), three types of PR modulators with antagonistic properties have been defined. In this study, we analyzed the in vitro characteristics of the PR antagonist
ZK 230211 in comparison to the classical antagonists
onapristone and
mifepristone. We focused on PR actions in genomic signaling pathways, including
DNA binding activity, nuclear localization and association with the
nuclear receptor corepressor (NCoR) as well as actions in non-genomic signaling, such as the activation of
c-Src kinase signaling and cyclin D1 gene promoter activity.
ZK 230211 represents a type of PR antagonist with increased inhibitory properties in comparison to
mifepristone and
onapristone. When liganded to the
progesterone receptor,
ZK 230211 induces a strong and persistent binding to its target response element (PRE) and increases NCoR recruitment in
CV-1 cells. Furthermore,
ZK 230211 displays less agonistic properties with regard to the association of PR
isoform B and the cytoplasmic
c-Src kinase in HeLa cells. It represses T47D cell cycle progression, in particular
estradiol-induced S phase entry. In summary, our studies demonstrate
ZK 230211 to be a type III
progesterone receptor antagonist which is characterized by very strong
DNA binding activity and strong antiproliferative effects in the
cancer cell lines HeLa and T47D.