title: Resistance to cisplatin and paclitaxel does not affect the sensitivity of human ovarian cancer cells to antiprogestin-induced cytotoxicity.
abstract: 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.
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South, Dakota, 414 East Clark Street, Vermillion, SD 57069, USA ; Present Address: Institute of Medicine and Experimental Biology of Cuyo, National Council for Scientific and Technical Research (CONICET), Mendoza, Argentina.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Gamarra-Luques
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South, Dakota, 414 East Clark Street, Vermillion, SD 57069, USA ; Present Address: Institute of Medicine and Experimental Biology of Cuyo, National Council for Scientific and Technical Research (CONICET), Mendoza, Argentina.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Hapon
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South, Dakota, 414 East Clark Street, Vermillion, SD 57069, USA.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: Goyeneche
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South, Dakota, 414 East Clark Street, Vermillion, SD 57069, USA.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Telleria
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004963:Estrenes / Q000494:pharmacology; D005260:Female; D005663:Furans / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D015735:Mifepristone / Q000494:pharmacology*; D009649:Norpregnadienes / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004963:Estrenes; D005663:Furans; D006727:Hormone Antagonists; D009649:Norpregnadienes; C076196:Org 31710; C461063:telapristone acetate; D015735:Mifepristone; C461062:CDB-4453; C094854:ulipristal; D017239:Paclitaxel; D002945:Cisplatin
keywords: Antiprogestins; Chemoresistance; Ovarian cancer