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Investigational New Drugs
Published in: Investigational New Drugs 3/2012

Open Access 01-06-2012 | PRECLINICAL STUDIES

Growth inhibition induced by antiprogestins RU-38486, ORG-31710, and CDB-2914 in ovarian cancer cells involves inhibition of cyclin dependent kinase 2

Authors: Alicia A. Goyeneche, Erin E. Seidel, Carlos M. Telleria

Published in: Investigational New Drugs | Issue 3/2012

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Summary

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 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.
Appendix
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Literature
1.
Spitz IM (2006) Progesterone receptor antagonists. Curr Opin Investig Drugs 7(10):882–890PubMed
2.
3.
4.
5.
Li D-Q, Wang Z-B, Bai J, Zhao J, Wang Y, Hu K, Du Y-H (2004) Effects of mifepristone on proliferation of human gastric adenocarcinoma cell line SGC-7901 in vitro. World J Gastroenterol 10(18):2628–2631PubMed
6.
Matsuda Y, Kawamoto K, Kiya K, Kurisu K, Sugiyama K, Uozumi T (1994) Antitumor effects of antiprogesterones on human meningioma cells in vitro and in vivo. J Neurosurg 80(3):527–534PubMedCrossRef
7.
Navo MA, Smith JA, Gaikwad A, Burke T, Brown J, Ramondetta LM (2008) In vitro evaluation of the growth inhibition and apoptosis effect of mifepristone (RU486) in human Ishikawa and HEC1A endometrial cancer cell lines. Cancer Chemother Pharmacol 62(3):483–489. doi:10.​1007/​s00280-007-0628-z PubMedCrossRef
8.
El Etreby MF, Liang Y, Johnson MH, Lewis RW (2000) Antitumor activity of mifepristone in the human LNCaP, LNCaP-C4, and LNCaP-C4-2 prostate cancer models in nude mice. Prostate 42(2):99–106PubMedCrossRef
9.
Musgrove EA, Lee CS, Cornish AL, Swarbrick A, Sutherland RL (1997) Antiprogestin inhibition of cell cycle progression in T-47D breast cancer cells is accompanied by induction of the cyclin-dependent kinase inhibitor p21. Mol Endocrinol 11(1):54–66PubMedCrossRef
10.
El Etreby MF, Liang Y, Wrenn RW, Schoenlein PV (1998) Additive effect of mifepristone and tamoxifen on apoptotic pathways in MCF-7 human breast cancer cells. Breast Cancer Res Treat 51(2):149–168PubMedCrossRef
11.
Yokoyama Y, Shinohara A, Takahashi Y, Wan X, Takahashi S, Niwa K, Tamaya T (2000) Synergistic effects of danazol and mifepristone on the cytotoxicity of UCN-01 in hormone-responsive breast cancer cells. Anticancer Res 20(5A):3131–3135PubMed
12.
Schoenlein PV, Hou M, Samaddar JS, Gaddy VT, Thangaraju M, Lewis J, Johnson M, Ganapathy V, Kallab A, Barrett JT (2007) Downregulation of retinoblastoma protein is involved in the enhanced cytotoxicity of 4-hydroxytamoxifen plus mifepristone combination therapy versus antiestrogen monotherapy of human breast cancer. Int J Oncol 31(3):643–655PubMed
13.
Gaddy VT, Barrett JT, Delk JN, Kallab AM, Porter AG, Schoenlein PV (2004) Mifepristone induces growth arrest, caspase activation, and apoptosis of estrogen receptor-expressing, antiestrogen-resistant breast cancer cells. Clin Cancer Res 10(15):5215–5225PubMedCrossRef
14.
Liang Y, Hou M, Kallab AM, Barrett JT, El Etreby F, Schoenlein PV (2003) Induction of antiproliferation and apoptosis in estrogen receptor negative MDA-231 human breast cancer cells by mifepristone and 4-hydroxytamoxifen combination therapy: a role for TGFbeta1. Int J Oncol 23(2):369–380PubMed
15.
16.
Jurado R, Lopez-Flores A, Alvarez A, Garcia-Lopez P (2009) Cisplatin cytotoxicity is increased by mifepristone in cervical carcinoma: an in vitro and in vivo study. Oncol Rep 22(5):1237–1245PubMed
17.
Rose FV, Barnea ER (1996) Response of human ovarian carcinoma cell lines to antiprogestin mifepristone. Oncogene 12(5):999–1003PubMed
18.
Goyeneche AA, Caron RW, Telleria CM (2007) Mifepristone inhibits ovarian cancer cell growth in vitro and in vivo. Clin Cancer Res 13(11):3370–3379PubMedCrossRef
19.
Freeburg EM, Goyeneche AA, Seidel EE, Telleria CM (2009) Resistance to cisplatin does not affect sensitivity of human ovarian cancer cell lines to mifepristone cytotoxicity. Cancer Cell Int 9:4. doi:10.​1186/​1475-2867-9-4 PubMedCrossRef
20.
Freeburg EM, Goyeneche AA, Telleria CM (2009) Mifepristone abrogates repopulation of ovarian cancer cells in between courses of cisplatin treatment. Int J Oncol 34(3):743–755PubMed
21.
Belanger A, Philibert D, Teutsch G (1981) Regio and stereospecific synthesis of 11 beta-substituted 19-norsteroids. Influence of 11 beta-substitution on progesterone receptor affinity - (1). Steroids 37(4):361–382. doi:0039-128X(81)90039-8 PubMedCrossRef
22.
Kloosterboer HJ, Deckers GH, Schoonen WG, Hanssen RG, Rose UM, Verbost PM, Hsiu JG, Williams RF, Hodgen GD (2000) Preclinical experience with two selective progesterone receptor modulators on breast and endometrium. Steroids 65(10–11):733–740. doi:10.​1016/​S0039-128X(00)001896-6 PubMedCrossRef
23.
Wiehle RD, Christov K, Mehta R (2007) Anti-progestins suppress the growth of established tumors induced by 7,12-dimethylbenz(a)anthracene: comparison between RU486 and a new 21-substituted-19-nor-progestin. Oncol Rep 18(1):167–174PubMed
24.
Xu Q, Takekida S, Ohara N, Chen W, Sitruk-Ware R, Johansson ED, Maruo T (2005) Progesterone receptor modulator CDB-2914 down-regulates proliferative cell nuclear antigen and Bcl-2 protein expression and up-regulates caspase-3 and poly(adenosine 5'-diphosphate-ribose) polymerase expression in cultured human uterine leiomyoma cells. J Clin Endocrinol Metab 90(2):953–961. doi:10.​1210/​jc.​2004-1569 PubMedCrossRef
25.
26.
Svensson EC, Markstrom E, Shao R, Andersson M, Billig H (2001) Progesterone receptor antagonists Org 31710 and RU 486 increase apoptosis in human periovulatory granulosa cells. Fertil Steril 76(6):1225–1231. doi:S0015-0282(01)02891-6 PubMedCrossRef
27.
Fraser M, Leung BM, Yan X, Dan HC, Cheng JQ, Tsang BK (2003) p53 is a determinant of X-linked inhibitor of apoptosis protein/Akt-mediated chemoresistance in human ovarian cancer cells. Cancer Res 63(21):7081–7088PubMed
28.
Yaginuma Y, Westphal H (1992) Abnormal structure and expression of the p53 gene in human ovarian carcinoma cell lines. Cancer Res 52(15):4196–4199PubMed
29.
30.
Yang ES, Burnstein KL (2003) Vitamin D inhibits G1 to S progression in LNCaP prostate cancer cells through p27Kip1 stabilization and Cdk2 mislocalization to the cytoplasm. J Biol Chem 278(47):46862–46868. doi:10.​1074/​jbc.​M306340200 PubMedCrossRef
31.
Brown KA, Roberts RL, Arteaga CL, Law BK (2004) Transforming growth factor-beta induces Cdk2 relocalization to the cytoplasm coincident with dephosphorylation of retinoblastoma tumor suppressor protein. Breast Cancer Res 6(2):R130–139. doi:10.​1186/​bcr762 PubMedCrossRef
32.
33.
34.
Zhao J, Kennedy BK, Lawrence BD, Barbie DA, Matera AG, Fletcher JA, Harlow E (2000) NPAT links cyclin E-Cdk2 to the regulation of replication-dependent histone gene transcription. Genes Dev 14(18):2283–2297PubMedCrossRef
35.
Lents NH, Keenan SM, Bellone C, Baldassare JJ (2002) Stimulation of the Raf/MEK/ERK cascade is necessary and sufficient for activation and Thr-160 phosphorylation of a nuclear-targeted CDK2. J Biol Chem 277(49):47469–47475. doi:10.​1074/​jbc.​M207425200 PubMedCrossRef
36.
Flores O, Wang Z, Knudsen KE, Burnstein KL (2010) Nuclear targeting of cyclin-dependent kinase 2 reveals essential roles of cyclin-dependent kinase 2 localization and cyclin E in vitamin D-mediated growth inhibition. Endocrinology 151(3):896–908. doi:10.​1210/​en.​2009-1116 PubMedCrossRef
37.
Sui L, Dong Y, Ohno M, Sugimoto K, Tai Y, Hando T, Tokuda M (2001) Implication of malignancy and prognosis of p27(kip1), Cyclin E, and Cdk2 expression in epithelial ovarian tumors. Gynecol Oncol 83(1):56–63PubMedCrossRef
38.
Rosen DG, Yang G, Cai KQ, Bast RC Jr, Gershenson DM, Silva EG, Liu J (2005) Subcellular localization of p27kip1 expression predicts poor prognosis in human ovarian cancer. Clin Cancer Res 11(2 Pt 1):632–637. doi:11/​2/​632 PubMed
39.
Singer JD, Gurian-West M, Clurman B, Roberts JM (1999) Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells. Genes Dev 13(18):2375–2387PubMedCrossRef
40.
Pajalunga D, Crescenzi M (2004) Regulation of cyclin E protein levels through E2F-mediated inhibition of degradation. Cell cycle (Georgetown Tex) 3(12):1572–1578. doi:1279 CrossRef
41.
Freemantle SJ, Liu X, Feng Q, Galimberti F, Blumen S, Sekula D, Kitareewan S, Dragnev KH, Dmitrovsky E (2007) Cyclin degradation for cancer therapy and chemoprevention. J Cell Biochem 102(4):869–877. doi:10.​1002/​jcb.​21519 PubMedCrossRef
42.
Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H (1999) p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27. Curr Biol 9(12):661–664. doi:S0960-9822(99)80290-5 PubMedCrossRef
43.
44.
45.
46.
47.
Huang H, Tindall DJ (2007) CDK2 and FOXO1: a fork in the road for cell fate decisions. Cell cycle (Georgetown Tex) 6(8):902–906. doi:4122 CrossRef
48.
Liang Y, Eid MA, El Etreby F, Lewis RW, Kumar MV (2002) Mifepristone-induced secretion of transforming growth factor beta1-induced apoptosis in prostate cancer cells. Int J Oncol 21(6):1259–1267PubMed
49.
Kamradt MC, Mohideen N, Vaughan AT (2000) RU486 increases radiosensitivity and restores apoptosis through modulation of HPV E6/E7 in dexamethasone-treated cervical carcinoma cells. Gynecol Oncol 77(1):177–182. doi:10.​1006/​gyno.​1999.​5724 PubMedCrossRef
50.
Bardon S, Vignon F, Montcourrier P, Rochefort H (1987) Steroid receptor-mediated cytotoxicity of an antiestrogen and an antiprogestin in breast cancer cells. Cancer Res 47(5):1441–1448PubMed
51.
Zhou H, Luo MP, Schonthal AH, Pike MC, Stallcup MR, Blumenthal M, Zheng W, Dubeau L (2002) Effect of reproductive hormones on ovarian epithelial tumors: I. Effect on cell cycle activity. Cancer Biol Ther 1(3):300–306. doi:10230130 PubMed
52.
Blumenthal M, Kardosh A, Dubeau L, Borok Z, Schonthal AH (2003) Suppression of the transformed phenotype and induction of differentiation-like characteristics in cultured ovarian tumor cells by chronic treatment with progesterone. Mol Carcinog 38(4):160–169. doi:10.​1002/​mc.​10155 PubMedCrossRef
Metadata
Title
Growth inhibition induced by antiprogestins RU-38486, ORG-31710, and CDB-2914 in ovarian cancer cells involves inhibition of cyclin dependent kinase 2
Authors
Alicia A. Goyeneche
Erin E. Seidel
Carlos M. Telleria
Publication date
01-06-2012
Publisher
Springer US
Published in
Investigational New Drugs / Issue 3/2012
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-011-9655-z

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