The online version of this article (doi:10.1186/1757-2215-7-45) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
CGL and CMT conceived and designed the experiments. AAG performed initial validation experiments with CDB-4124 derivatives. CGL developed the drug-resistant cell lines and performed a comprehensive study on their responses to a panel of antiprogestins. MBH contributed with the western blot assays. CMT contributed with the reagents, materials and analysis tools. CGL and CMT wrote the paper. All authors approved the final version of the manuscript.
Antiprogestin compounds have been shown to be effective in blocking the growth of ovarian cancer cells of different genetic backgrounds. Herein we studied the anti-ovarian cancer effect of a series of antiprogestins sharing the chemical backbone of the most characterized antiprogestin, mifepristone, but with unique modifications in position C-17 of the steroid ring. We assessed the effect of mifepristone-like antiprogestins on the growth of ovarian cancer cells sensitive to the standard combination therapy cisplatin-paclitaxel or made double-resistant upon six cycles of pulse-selection with the drugs used at clinically relevant concentrations and exposure times.
IGROV-1 and SKOV-3 cells were pulsed with 20 μM cisplatin for 1 h followed by 100 nM paclitaxel for 3 h once a week for six weeks. The cells that did not die and repopulate the culture after the chemotherapies were termed Platinum-Taxane-EScape cells (PTES). Parental cells were compared against their PTES derivatives in their responses to further platinum-taxane treatments. Moreover, both ovarian cancer cells and their PTES siblings were exposed to escalating doses of the various antiprogestin derivatives. We assessed cell growth, viability and sub-G1 DNA content using microcapillary cytometry. Cyclin-dependent kinase inhibitors p21cip1 and p27kip1 and cleavage of downstream caspase-3 substrate PARP were used to assess whether cell fate, as a consequence of treatment, was limited to cytostasis or progressed to lethality.
Cells subjected to six pulse-selection cycles of cisplatin-paclitaxel gave rise to sibling derivatives that displayed ~2-7 fold reduction in their sensitivities to further chemotherapy. However, regardless of the sensitivity the cells developed to the combination cisplatin-paclitaxel, they displayed similar sensitivity to the antiprogestins, which blocked their growth in a dose-related manner, with lower concentrations causing cytostasis, and higher concentrations causing lethality.
Antiprogestins carrying a backbone similar to mifepristone are cytotoxic to ovarian cancer cells in a manner that does not depend on the sensitivity the cells have to the standard ovarian cancer chemotherapeutics, cisplatin and paclitaxel. Thus, antiprogestin therapy could be used to treat ovarian cancer cells showing resistance to both platinum and taxanes.
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Vaughan S, Coward JI, Bast RC Jr, Berchuck A, Berek JS, Brenton JD, Coukos G, Crum CC, Drapkin R, Etemadmoghadam D, Friedlander M, Gabra H, Kaye SB, Lord CJ, Lengyel E, Levine DA, McNeish IA, Menon U, Mills GB, Nephew KP, Oza AM, Sood AK, Stronach EA, Walczak H, Bowtell DD, Balkwill FR: Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer 2011, 11(10):719–725. 10.1038/nrc3144 PubMedCentralCrossRefPubMed
Telleria CM, Goyeneche AA: Antiprogestins in Ovarian Cancer. In Ovarian Cancer -Clinical and Therapeutic Perspectives. Chapter 11 edition. Edited by: Farghaly S. Rijeka, Croatia: InTechopen; 2012.
Kurata T, Tamura T, Shinkai T, Ohe Y, Kunitoh H, Kodama T, Kakinuma R, Matsumoto T, Kubota K, Omatsu H, Nishiwaki Y, Saijo N: Phase I and pharmacological study of paclitaxel given over 3 h with cisplatin for advanced non-small cell lung cancer. Jpn J Clin Oncol 2001, 31(3):93–99. 10.1093/jjco/hye022 CrossRefPubMed
Langdon SP, Lawrie SS, Hay FG, Hawkes MM, McDonald A, Hayward IP, Schol DJ, Hilgers J, Leonard RC, Smyth JF: Characterization and properties of nine human ovarian adenocarcinoma cell lines. Cancer Res 1988, 48(21):6166–6172. PubMed
MdDermott M, Eustace AJ, Busschots S, Breen L, Crown J, Clynes M, O'Donovan N, Stordal B: In vitro development of chemotherapy and targeted therapy drug-resistant cancer cell lines: a practical guide with case studies. Frontiers Oncol 2014, 4: 40.
Katano K, Kondo A, Safaei R, Holzer A, Samimi G, Mishima M, Kuo YM, Rochdi M, Howell SB: Acquisition of resistance to cisplatin is accompanied by changes in the cellular pharmacology of copper. Cancer Res 2002, 62(22):6559–6565. PubMed
Ledermann JA, Kristeleit RS: Optimal treatment for relapsing ovarian cancer. Ann Oncol 2010, 21(Suppl 7):vii218-vii222. PubMed
Yan XD, Li M, Yuan Y, Mao N, Pan LY: Biological comparison of ovarian cancer resistant cell lines to cisplatin and Taxol by two different administrations. Oncol Rep 2007, 17(5):1163–1169. PubMed
Lu X, Errington J, Curtin NJ, Lunec J, Newell DR: The impact of p53 status on cellular sensitivity to antifolate drugs. Clin Cancer Res 2001, 7(7):2114–2123. PubMed
Siddik ZH, Mims B, Lozano G, Thai G: Independent pathways of p53 induction by cisplatin and X-rays in a cisplatin-resistant ovarian tumor cell line. Cancer Res 1998, 58(4):698–703. PubMed
Debernardis D, Sire EG, De Feudis P, Vikhanskaya F, Valenti M, Russo P, Parodi S, D'Incalci M, Broggini M: p53 status does not affect sensitivity of human ovarian cancer cell lines to paclitaxel. Cancer Res 1997, 57(5):870–874. PubMed
Righetti SC, Perego P, Corna E, Pierotti MA, Zunino F: Emergence of p53 mutant cisplatin-resistant ovarian carcinoma cells following drug exposure: spontaneously mutant selection. Cell Growth Differ 1999, 10(7):473–478. PubMed
Yaginuma Y, Westphal H: Abnormal structure and expression of the p53 gene in human ovarian carcinoma cell lines. Cancer Res 1992, 52(15):4196–4199. PubMed
O'Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, Scudiero DA, Monks A, Sausville EA, Weinstein JN, Friend S, Fornace AJ Jr, Kohn KW: Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res 1997, 57(19):4285–4300. PubMed
Leonhardt SA, Edwards DP: Mechanism of action of progesterone antagonists. Exp Biol Med (Maywood) 2002, 227(11):969–980.
Attardi BJ, Burgenson J, Hild SA, Reel JR: In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone. J Steroid Biochem Mol Biol 2004, 88(3):277–288. 10.1016/j.jsbmb.2003.12.004 CrossRefPubMed
Tieszen CR, Goyeneche AA, Brandhagen BN, Ortbahn CT, Telleria CM: Antiprogestin mifepristone inhibits the growth of cancer cells of reproductive and non- reproductive origin regardless of progesterone receptor expression. BMC Cancer 2011, 11: 207. 10.1186/1471-2407-11-207 PubMedCentralCrossRefPubMed
Liang Y, Hou M, Kallab AM, Barrett JT, El Etreby F, Schoenlein PV: 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 2003, 23(2):369–380. PubMed
- Resistance to cisplatin and paclitaxel does not affect the sensitivity of human ovarian cancer cells to antiprogestin-induced cytotoxicity
Carlos D Gamarra-Luques
Maria B Hapon
Alicia A Goyeneche
Carlos M Telleria
- BioMed Central
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