Antiprogestins have been largely utilized in reproductive medicine, yet their repositioning for oncologic use is rapidly emerging. In this study we investigated the molecular mediators of the anti-
ovarian cancer activity of the structurally related antiprogestins
RU-38486,
ORG-31710 and
CDB-2914. We studied the responses of wt p53 OV2008 and p53 null SK-OV-3 cells to varying doses of
RU-38486,
ORG-31710 and
CDB-2914. The
steroids inhibited the growth of both cell lines with a potency of
RU-38486 >
ORG-31710 >
CDB-2914, and were
cytostatic at lower doses but lethal at higher concentrations. Antiprogestin-induced lethality associated with morphological features of apoptosis, hypodiploid
DNA content, DNA fragmentation, and cleavage of executer
caspase substrate PARP. Cell death ensued despite
RU-38486 caused transient up-regulation of anti-apoptotic Bcl-2,
ORG-31710 induced transient up-regulation of inhibitor of apoptosis XIAP, and
CDB-2914 up-regulated both XIAP and Bcl-2. The antiprogestins induced accumulation of Cdk inhibitors p21(cip1) and p27(kip1) and increased association of p21(cip1) and p27(kip1) with Cdk-2. They also promoted nuclear localization of p21(cip1) and p27(kip1), reduced the nuclear abundances of Cdk-2 and
cyclin E, and blocked the activity of Cdk-2 in both nucleus and cytoplasm. The cytotoxic potency of the antiprogestins correlated with the magnitude of the inhibition of Cdk-2 activity, ranging from G1 cell cycle arrest towards cell death. Our results suggest that, as a consequence of their
cytostatic and lethal effects, antiprogestin
steroids of well-known
contraceptive properties emerge as attractive new agents to be repositioned for
ovarian cancer therapeutics.