Resistance to cisplatin and paclitaxel does not affect the sensitivity of human ovarian cancer cells to antiprogestin-induced cytotoxicity

Journal of Ovarian Research

Carlos M Telleria²  Alicia A Goyeneche²  Maria B Hapon¹  Carlos D Gamarra-Luques¹ 

[1] Present Address: Institute of Medicine and Experimental Biology of Cuyo, National Council for Scientific and Technical Research (CONICET), Mendoza, Argentina;Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South, Dakota, 414 East Clark Street, Vermillion, SD 57069, USA

关键词: Antiprogestins;    Chemoresistance;    Ovarian cancer;   

Others  :  801500
DOI  :  10.1186/1757-2215-7-45

 received in 2014-03-12, accepted in 2014-04-21,  发布年份 2014

【 摘 要 】

Background

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.

Methods

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 p21^cip1 and p27^kip1 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.

Results

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.

Conclusions

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.

【 授权许可】

   
2014 Gamarra-Luques et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Romero I, Bast RC Jr: Minireview: human ovarian cancer: biology, current management, and paths to personalizing therapy. Endocrinology 2012, 153(4):1593-1602.
• [2]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.
• [3]Bast RC Jr, Hennessy B, Mills GB: The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer 2009, 9(6):415-428.
• [4]Kurman RJ, Shih Ie M: Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer–shifting the paradigm. Hum Pathol 2011, 42(7):918-931.
• [5]Coleman RL, Monk BJ, Sood AK, Herzog TJ: Latest research and treatment of advanced-stage epithelial ovarian cancer. Nat Rev Clin Oncol 2013, 10(4):211-224.
• [6]Bast RC Jr: Molecular approaches to personalizing management of ovarian cancer. Ann Oncol 2011, 22(Suppl 8):viii5.
• [7]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.
• [8]Goyeneche AA, Caron RW, Telleria CM: Mifepristone inhibits ovarian cancer cell growth in vitro and in vivo. Clin Cancer Res 2007, 13(11):3370-3379.
• [9]Freeburg EM, Goyeneche AA, Telleria CM: Mifepristone abrogates repopulation of ovarian cancer cells in between courses of cisplatin treatment. Int J Oncol 2009, 34(3):743-755.
• [10]Gamarra-Luques CD, Goyeneche AA, Hapon MB, Telleria CM: Mifepristone prevents repopulation of ovarian cancer cells escaping cisplatin-paclitaxel therapy. BMC Cancer 2012, 12:200. BioMed Central Full Text
• [11]Goyeneche AA, Seidel EE, Telleria CM: Growth inhibition induced by antiprogestins RU-38486, ORG-31710, and CDB-2914 in ovarian cancer cells involves inhibition of cyclin dependent kinase 2. Invest New Drugs 2012, 30(3):967-980.
• [12]Freeburg EM, Goyeneche AA, Seidel EE, Telleria CM: Resistance to cisplatin does not affect sensitivity of human ovarian cancer cell lines to mifepristone cytotoxicity. Cancer Cell Int 2009, 9:4. BioMed Central Full Text
• [13]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.
• [14]Himmelstein KJ, Patton TF, Belt RJ, Taylor S, Repta AJ, Sternson LA: Clinical kinetics on intact cisplatin and some related species. Clin Pharmacol Ther 1981, 29(5):658-664.
• [15]du Bois A, Luck HJ, Buser K, Meerpohl HG, Sessa C, Klaassen U, Meden H, Bochtler H, Diergarten K: Extended phase II study of paclitaxel as a 3-h infusion in patients with ovarian cancer previously treated with platinum. Eur J Cancer 1997, 33(3):379-384.
• [16]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.
• [17]Cooke SL, Ng CK, Melnyk N, Garcia MJ, Hardcastle T, Temple J, Langdon S, Huntsman D, Brenton JD: Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma. Oncogene 2010, 29(35):4905-4913.
• [18]Ormerod MG, O'Neill C, Robertson D, Kelland LR, Harrap KR: cis- Diamminedichloroplatinum(II)-induced cell death through apoptosis in sensitive and resistant human ovarian carcinoma cell lines. Cancer Chemother Pharmacol 1996, 37(5):463-471.
• [19]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.
• [20]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.
• [21]Ledermann JA, Kristeleit RS: Optimal treatment for relapsing ovarian cancer. Ann Oncol 2010, 21(Suppl 7):vii218-vii222.
• [22]Stordal B, Hamon M, McEneaney V, Roche S, Gillet JP, O'Leary JJ, Gottesman M, Clynes M: Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein. PLoS One 2012, 7(7):e40717.
• [23]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.
• [24]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.
• [25]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.
• [26]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.
• [27]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.
• [28]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.
• [29]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.
• [30]Berglind H, Pawitan Y, Kato S, Ishioka C, Soussi T: Analysis of p53 mutation status in human cancer cell lines: a paradigm for cell line cross-contamination. Cancer Biol Ther 2008, 7(5):699-708.
• [31]Hamroun D, Kato S, Ishioka C, Claustres M, Beroud C, Soussi T: The UMD TP53 database and website: update and revisions. Hum Mutat 2006, 27(1):14-20.
• [32]Belanger A, Philibert D, Teutsch G: Regio and stereospecific synthesis of 11 beta- substituted 19-norsteroids. Influence of 11 beta-substitution on progesterone receptor affinity - (1). Steroids 1981, 37(4):361-382.
• [33]Benagiano G, Bastianelli C, Farris M: Selective progesterone receptor modulators 1: use during pregnancy. Expert Opin Pharmacother 2008, 9(14):2459-2472.
• [34]Moller C, Hoffmann J, Kirkland TA, Schwede W: Investigational developments for the treatment of progesterone-dependent diseases. Expert Opin Investig Drugs 2008, 17(4):469-479.
• [35]Attardi BJ, Burgenson J, Hild SA, Reel JR, Blye RP: CDB-4124 and its putative monodemethylated metabolite, CDB-4453, are potent antiprogestins with reduced antiglucocorticoid activity: in vitro comparison to mifepristone and CDB-2914. Mol Cell Endocrinol 2002, 188(1–2):111-123.
• [36]Leonhardt SA, Edwards DP: Mechanism of action of progesterone antagonists. Exp Biol Med (Maywood) 2002, 227(11):969-980.
• [37]Telleria CM: Drug Repurposing for Cancer Therapy. J Cancer Sci Ther 2012, 4(7):ix-xi.
• [38]Spitz IM: Clinical utility of progesterone receptor modulators and their effect on the endometrium. Curr Opin Obstet Gynecol 2009, 21(4):318-324.
• [39]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.
• [40]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. BioMed Central Full Text
• [41]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.
• [42]Kadmiel M, Cidlowski JA: Glucocorticoid receptor signaling in health and disease. Trends Pharmacol Sci 2013, 34(9):518-530.
• [43]Lewis-Tuffin LJ, Jewell CM, Bienstock RJ, Collins JB, Cidlowski JA: Human glucocorticoid receptor beta binds RU-486 and is transcriptionally active. Mol Cell Biol 2007, 27(6):2266-2282.