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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Journal of Ovarian Research 1/2014

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

Zeitschrift:
Journal of Ovarian Research > Ausgabe 1/2014
Autoren:
Carlos D Gamarra-Luques, Maria B Hapon, Alicia A Goyeneche, Carlos M Telleria
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1757-2215-7-45) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

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.

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 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.

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.
Zusatzmaterial
Authors’ original file for figure 1
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Authors’ original file for figure 2
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Authors’ original file for figure 5
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Authors’ original file for figure 6
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Literatur
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