Resistance to cisplatin does not affect sensitivity of human ovarian cancer cell lines to mifepristone cytotoxicity

Abstract

Background: The prototypical antiprogestin mifepristone exhibits potent growth inhibition activity towards ovarian cancer cells in vitro and in vivo. The aim of this research was to establish whether mifepristone is capable of inhibiting cell proliferation and inducing apoptotic cell death regardless of the degree of sensitivity ovarian cancer cells exhibit to cisplatin.

Antiprogestins in Ovarian Cancer

“…Antiprogestin mifepristone is toxic towards ovarian cancer cells, with cytostasis manifested at lower micromolar concentrations and lethality taking place when the compound is used at higher micromolar doses (Freeburg et al,2009a;Goyeneche et al,2007;Goyeneche et al,2011;Tieszen et al,2011). When mifepristone was used at doses up to 20 M, the effect was limited to cytostasis demonstrated by the reversibility of the growth inhibition observed when the drug was removed from the culture media, in association with the lack of measurable cell death (Goyeneche et al,2007).…”

“…We showed that cell cultures exposed to mifepristone after cisplatin had a remarkable increase in the percentage of cells expressing the cell death marker cleaved poly (ADP-ribose) polymerase (PARP) and the mitotic marker phospho-histone H3 suggesting that mifepristone potentiates cisplatin lethality and that the cells likely die as a consequence of mitotic failure (Freeburg et al,2009b). We also reported that the effect of mifepristone in ovarian cancer cells is independent of p53 functionality and platinum sensitivity (Freeburg et al,2009a), making mifepristone an even more interesting chemotherapeutic candidate for ovarian cancer as the majority of tumors in relapsing patients are platinum resistant and p53 mutant (Ozols,2006b). Finally, we have shown in ovarian cancer cells that mifepristone potentiates the lethality of otherwise sub-lethal doses of cisplatin, and synergizes with cisplatin growth inhibiting ovarian cancer cells of different genetic backgrounds and platinum sensitivities (Gamarra-Luques&Telleria,2010).…”

“…When mifepristone was used at doses up to 20 M, the effect was limited to cytostasis demonstrated by the reversibility of the growth inhibition observed when the drug was removed from the culture media, in association with the lack of measurable cell death (Goyeneche et al,2007). In all ovarian cancer cell lines we investigated, concentrations of mifepristone 30 M or higher were lethal (Freeburg et al,2009a;Goyeneche et al,2011;Tieszen et al,2011). This lethality was illustrated by the reduced viability of the cells, the increase in cellular particles with hypodiploid fragmented DNA content, and the cleavage of the cell death associated caspase, caspase-3, in parallel with the cleavage of the widely accepted marker of cell death and a substrate for caspase-3, PARP (Scovassi&Poirier,1999).…”

Progesterone Resistance and Targeting the Progesterone Receptors: A Therapeutic Approach to Endometriosis

“…In each case, the intrauterine administration resulted in the characteristic inhibition of normal menstrual bleeding, atrophy of endometrial spiral arterioles and functionalis thickness, consistent with observations from systemic administration (Figure 2). The mechanism of attenuation of estradiol effects on the endometrium is not well understood, and although steroidal PRAs appear to block cell proliferation in various in vitro cell-based systems, the concentrations needed for this effect are considerably greater than those which elicit the effect in vivo (Freeburg et al, 2009a;Goyeneche et al, 2007;Murphy et al, 2000;Ohara et al, 2007;. One clue to a potential mechanism has emerged from observations of elevated endometrial androgen receptor (AR) expression (Narvekar et al, 2004;Slayden & Brenner, 2003) following PRA administration and the known effects of AR modulators (e.g.…”

Aqueous Extract of Prosopis strombulifera (LAM) BENTH Induces Cytotoxic Effects against Tumor Cell Lines without Systemic Alterations in BALB/c Mice

“…Cells were then counted in a Neubauer haemocytometer chamber using a clear-field microscopy. Concentration of extract needed to achieve 50% of growth inhibition is indicated as IC 50 , while extract concentration where 50% cell death was observed is indicated as LC 50 [15,16]. Assays were performed three times in triplicate.…”