SummaryAntiprogestins 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 p21cip1 and p27kip1 and increased association of p21cip1 and p27kip1 with Cdk-2. They also promoted nuclear localization of p21cip1 and p27kip1, 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10637-011-9655-z) contains supplementary material, which is available to authorized users.

Background: The prototypical antiprogestin mifepristone exhibits potent growth inhibition activity towards ovarian cancer cells in vitro and in vivo. The aim of this research was to establish whether mifepristone is capable of inhibiting cell proliferation and inducing apoptotic cell death regardless of the degree of sensitivity ovarian cancer cells exhibit to cisplatin.

Ovarian cancer (OCa) is the most deadly of the female reproductive tract and new therapeutic interventions for OCa patients are needed. We previously demonstrated that the prototypical antiprogestin mifepristone (MF; a.k.a. RU38486) has potent anti-OCa activity in both platinum (Pt)-sensitive and Pt-resistant cells and regardless of p53 genetic background. In this study we compared the anti-OCa efficacy of pharmacological and supra-pharmacological doses of MF to that of two antiprogestins structurally related, named ORG-31710 and Ulipristal (CDB-2914). We studied the response of wt p53 OV2008 and p53 null SK-OV-3 cells to varying doses of MF, ORG-31710 and CDB-2914. The 3 steroids inhibited growth of both cell lines with a potency of MF>ORG-31710>CDB-2914, were cytostatic at pharmacological doses, but lethal at supra-pharmacological doses. At cytostatic doses the antiprogestins induced G1 cell cycle arrest, accumulation of cyclin dependent kinase (Cdk) inhibitors p21cip1 and p27kip1, and increased association of p21cip1 and p27kip1 with Cdk2. Further, the antiprogestins promoted nuclear localization of p21cip1 and p27kip1, reduced the nuclear abundance of Cdk2 and cyclin E, and blocked Cdk2 activity in both nucleus and cytoplasm. The cytostatic potency of the antiprogestins correlated with the magnitude of the inhibition of Cdk2 activity. Supra-pharmacological doses of the antiprogestins killed OCa cells with some differences among the compounds. MF- and CDB-2914-induced cell death associated with morphological features of apoptosis, whereas that of ORG-31710 had characteristics of both apoptosis and necrosis. In OV2008 cells, MF-induced death was accompanied by caspase-3 activation, cleavage of PARP, downregulation of XIAP and cleavage of p27kip1, yet it occurred in the presence of high levels of Bcl-2. Cell death induced by ORG-31710 associated with PARP cleavage in the absence of caspase-3 cleavage, without changes in XIAP and Bcl-2 levels. Finally death induced by CDB-2914 associated with cleavage and upregulation of PARP, upregulation of Bcl-2, without changes in XIAP levels. The efficacy of antiprogestins as cytotoxic agents was not related to the basal expression of cognate progesterone receptors (PR) A and B. OV2008 cells expressed PR-A and PR-B proteins at one fourth of the levels of MCF-7 breast cancer cells, whereas SK-OV-3 cells showed almost no PR proteins. The two cell lines expressed glucocorticoid receptors (GR) alpha and beta, making these receptors potential mediators of antiprogestin-induced cytotoxicity. Due to their cytostatic and lethal properties antiprogestins originally designed for contraceptive purposes emerge as attractive new agents to treat OCa intrinsically resistant to clinically achievable doses of Pt derivatives, or recurrent Pt-resistant OCa. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 718.