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

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.

Glucocorticoid receptor activation inhibits chemotherapy-induced cell death in high-grade serous ovarian carcinoma

“…Telleria et al . previously reported that mifepristone treatment of OvCa cell lines at the much higher concentrations of 10-20 μM (versus 1 μM used in our studies) causes cell cycle arrest (27) and cytostasis (28). These authors also noted that the growth inhibitory effect of mifepristone did not require PR expression.…”

Activation of CD1d-restricted natural killer T cells can inhibit cancer cell proliferation during chemotherapy by promoting the immune responses in murine mesothelioma

“…Anti-tumor effect can be improved if this process could be effectively inhibited. Previous studies of ours and others demonstrated that specific inhibitors and immunoenhancing agents can inhibit cancer cell repopulation in a variety of cancers in animal models [4][5][6]. This concept has been applied to malignant pleural mesothelioma (MPM), which is a rare but aggressive cancer with poor prognosis.…”

Molecular Pathways: Targeting Cancer Stem Cells Awakened by Chemotherapy to Abrogate Tumor Repopulation

“…The fact that celecoxib is efficacious in improving chemotherapeutic response in a primary xenograft model derived from an original patient who failed chemotherapy, this provided convincing proof-of-concept evidence for testing such adjuvant therapeutic approaches with comparable concepts in other preclinical models and subsequent human clinical trials. Indeed, other approaches that block tumor repopulation (although not specifically targeting cancer stem cells) has been proven effective to enhance chemotherapeutic response in xenograft models of ovarian (35–37), glioma (38), breast (39, 40), prostate cancer (40) and mesothelioma (41). …”