Mifepristone prevents repopulation of ovarian cancer cells escaping cisplatin-paclitaxel therapy

Carlos D Gamarra-Luques,Carlos M Telleria,Alicia A Goyeneche,Maria B Hapon

doi:10.1186/1471-2407-12-200

Abstract

BackgroundAdvanced 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.MethodsWe 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.ResultsFour 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.ConclusionsCytostatic 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.

Highlights

Advanced ovarian cancer is treated with cytoreductive surgery and combination platinum- and taxane-based chemotherapy
Exposure of ovarian cancer cells to cisplatin and paclitaxel induces substantial growth inhibition and lethality that are either unaffected or enhanced by chronic presence of a cytostatic dose of mifepristone after removal of the cytotoxic agents To study whether mifepristone is capable of improving the efficacy of cisplatin when the platinating agent is combined with paclitaxel, we set up a preclinical in vitro model system using exposure times and concentration ranges known to cause lethality [25,26]
Cells treated with cisplatin and paclitaxel were largely affected in their growth capacity regardless of their genetic backgrounds, confirming in vitro their combined efficacy shown in the clinic

Summary

Introduction

Advanced ovarian cancer is treated with cytoreductive surgery and combination platinum- and taxane-based chemotherapy. Because early detection biomarkers are not yet available and the symptomatology is vague, the disease is usually diagnosed at a late stage when growths have extended within the peritoneal cavity [2,3,4] At this point, patients usually undergo cytoreductive surgery followed by platinum plus taxane-based chemotherapy [1,3]. In the 1990s a microtubule stabilizer, paclitaxel, was shown to potentiate cisplatin-based therapy in ovarian cancer patients with better efficacy than cisplatincyclophosphamide [8,9]. Since these clinical trials, only minor variations in the standard chemotherapeutic schedule for ovarian cancer patients have been implemented. Data worldwide concur that in the past 20 years there has been little change in the 5-year survival rates post-diagnosis of patients with ovarian cancer [1]

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