Mifepristone prevents repopulation of ovarian cancer cells escaping cisplatin-paclitaxel therapy.
BACKGROUND
Advanced ovarian cancer is treated with cytoreductive surgery and combination platinum- and taxane-based chemotherapy. Although most patients have acute clinical response to this strategy, the disease ultimately recurs. In this work we questioned whether the synthetic steroid mifepristone, which as monotherapy inhibits the growth of ovarian cancer cells, is capable of preventing repopulation of ovarian cancer cells if given after a round of lethal cisplatin-paclitaxel combination treatment.


METHODS
We established an in vitro approach wherein ovarian cancer cells with various sensitivities to cisplatin or paclitaxel were exposed to a round of lethal doses of cisplatin for 1 h plus paclitaxel for 3 h. Thereafter, cells were maintained in media with or without mifepristone, and short- and long-term cytotoxicity was assessed.


RESULTS
Four days after treatment the lethality of cisplatin-paclitaxel was evidenced by reduced number of cells, increased hypodiploid DNA content, morphological features of apoptosis, DNA fragmentation, and cleavage of caspase-3, and of its downstream substrate PARP. Short-term presence of mifepristone either enhanced or did not modify such acute lethality. Seven days after receiving cisplatin-paclitaxel, cultures showed signs of relapse with escaping colonies that repopulated the plate in a time-dependent manner. Conversely, cultures exposed to cisplatin-paclitaxel followed by mifepristone not only did not display signs of repopulation following initial chemotherapy, but they also had their clonogenic capacity drastically reduced when compared to cells repopulating after cisplatin-paclitaxel.


CONCLUSIONS
Cytostatic concentrations of mifepristone after exposure to lethal doses of cisplatin and paclitaxel in combination blocks repopulation of remnant cells surviving and escaping the cytotoxic drugs.
Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, 414 East Clark Street, Vermillion, SD, USA.
Carlos D
CD
Gamarra-Luques
Alicia A
AA
Goyeneche
Maria B
MB
Hapon
Carlos M
CM
Telleria
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D006727:Hormone Antagonists; D015735:Mifepristone; D017239:Paclitaxel; D002945:Cisplatin