Antiprogestin mifepristone inhibits the growth of cancer cells of reproductive and non-reproductive origin regardless of progesterone receptor expression

Abstract

BackgroundMifepristone (MF) has been largely used in reproductive medicine due to its capacity to modulate the progesterone receptor (PR). The study of MF has been expanded to the field of oncology; yet it remains unclear whether the expression of PR is required for MF to act as an anti-cancer agent. Our laboratory has shown that MF is a potent inhibitor of ovarian cancer cell growth. In this study we questioned whether the growth inhibitory properties of MF observed in ovarian cancer cells would translate to other cancers of reproductive and non-reproductive origin and, importantly, whether its efficacy is related to the expression of cognate PR.MethodsDose-response experiments were conducted with cancer cell lines of the nervous system, breast, prostate, ovary, and bone. Cultures were exposed to vehicle or increasing concentrations of MF for 72 h and analysed for cell number and cell cycle traverse, and hypodiploid DNA content characteristic of apoptotic cell death. For all cell lines, expression of steroid hormone receptors upon treatment with vehicle or cytostatic doses of MF for 24 h was studied by Western blot, whereas the activity of the G1/S regulatory protein Cdk2 in both treatment groups was monitored in vitro by the capacity of Cdk2 to phosphorylate histone H1.ResultsMF growth inhibited all cancer cell lines regardless of tissue of origin and hormone responsiveness, and reduced the activity of Cdk2. Cancer cells in which MF induced G1 growth arrest were less susceptible to lethality in the presence of high concentrations of MF, when compared to cancer cells that did not accumulate in G1. While all cancer cell lines were growth inhibited by MF, only the breast cancer MCF-7 cells expressed cognate PR.ConclusionsAntiprogestin MF inhibits the growth of different cancer cell lines with a cytostatic effect at lower concentrations in association with a decline in the activity of the cell cycle regulatory protein Cdk2, and apoptotic lethality at higher doses in association with increased hypodiploid DNA content. Contrary to common opinion, growth inhibition of cancer cells by antiprogestin MF is not dependent upon expression of classical, nuclear PR.

Progesterone Inhibits the Growth of Human Neuroblastoma: In Vitro and In Vivo Evidence

“…But the proliferative effect was significantly decreased (P < 0.05) and cell death was observed at high concentrations of P4 (5,10,20,40 and 80 μmol/L) at both 3 and 6 d. The addition of RU486 blocked the proliferative effect of low P4 concentrations but failed to block the cytotoxic effect of P4 at high concentrations. RU486 alone showed a P4 mimetic effect at high concentrations but, when P4 and RU486 were combined, a marked enhancement of the toxic effect was observed.…”

“…A single 48-h exposure to P4 at a range of concentrations (0.1, 1, 5, 10, 20, 40 and 80 μmol/L) caused significant (P < 0.05) cell death at higher concentrations (20,40 and 80 μmol/L) in PC-12 cells, but no toxicity was observed at lower concentrations (0.1, 1, 5 and 10 μmol/L) (Figure 1A). SK-N-AS cells exposed to P4 produced a U-shaped response curve for viability.…”

“…We recently reported that a combination of P4 with vitamin D hormone affords better neuroprotection than P4 alone in an in vitro excitotoxicity model of brain damage (2). In the course of establishing this experimental model, we observed that high concentrations of P4 (20,40 and 80 μmol/L) were neuroprotective against a cytotoxic challenge in primary cortical neurons but caused significant cell death in a tumor cell line, PC-12 (pheochromocytoma). These observations led us to consider the possibility that P4 may have selectively toxic effects capable of inhibiting neuro blastoma growth.…”

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

“…Given the anti-proliferative effects observed in vitro and in vivo for PRAs (Freeburg et al, 2009b;Goyeneche et al, 2007;Ohara et al, 2007;Poole et al, 2006;Tieszen et al, 2011), the broader utility of this class in treating other benign and malignant growth conditions has not gone unnoticed Robertson et al, 1999;Rocereto et al, 2000;Wilkens et al, 2008). In the closely related condition of uterine fibroids, small studies have demonstrated a reduction in myoma volume and uterine bleeding with asoprisnil and RU-486 (Chabbert-Buffet et al, 2005;DeManno et al, 2003;Fiscella et al, 2006).…”

“…Ablation of PR-B promoted cellular proliferation, by approximately 20% compared with control, supporting the notion that PR-B acts as a break on progesterone function. It is noteworthy that breast and endometrial malignancy is often accompanied by disruption of PR-A and PR-B expression or altered functional PR responses (Arnett-Mansfield et al, 2004;De Vivo et al, 2002;Kobayashi et al, 2010;McGowan et al, 2004), an observation which has triggered interest in the potential utility of PRAs for oncology (Fuhrmann et al, 2000;Poole et al, 2006;Tieszen et al, 2011;Wiehle et al, 2011). Recent evidence has also confirmed the existence of a functional third isoform, PR-C which lacks AF-2 and AF-3 domains and appears to act as a sink for progesterone and have a function in regulating the onset of parturition (Condon et al, 2006).…”