Abstract 718: Antiprogestins are cytostatic at pharmacological concentrations and lethal at suprapharmacological concentrations to ovarian cancer cells

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 p21^cip1 and p27^kip1, and increased association of p21^cip1 and p27^kip1 with Cdk2. Further, the antiprogestins promoted nuclear localization of p21^cip1 and p27^kip1, 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 p27^kip1, 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.