MCF-7 cell apoptosis and cell cycle arrest: non-genomic effects of progesterone and mifepristone (RU-486).

The pharmacology of progestins includes actions initiated by various cellular targets, including classic receptors characterized as nuclear transcription factors (nPR), G-protein-coupled membrane receptors (mPR), enzymes, membrane channels and transporters. The effects initiated by targets other than nPR are termed non-genomic and there is an increasing recognition that these effects also play an important role in the regulation of cell growth. The nPR-positive breast cancer (MCF-7) and the nPR-negative uterine cervix cancer (C4-I) cell lines were exposed to progesterone (PG) and mifepristone (MF) during a culture period of 96 h. Daily cell count, cell cycle analysis and apoptosis assay were performed. It was possible to separate the nPR initiated effects (growth stimulation) from the non-genomic effects (growth inhibition) in the MCF-7 cells. Below 1 μM PG treatment gave a small, but distinct increase in cell density which was effectively blocked by MF. Such an effect was absent from the nPR-negative C4-I cells. For a range of concentrations between 1 μM and 100 μM, the effect of both PG and MF developed over time and showed concentration dependency. The PG concentrations needed to reduce cell density by 50% (IC(50)) were 12.8 ± 1.1 μM and 6.5 ± 0.2 μM for the MCF-7 and C4-I cells, respectively. MF appeared to be equally or slightly more potent, with respective IC(50) values of 6.9 ± 0.5 μM and 5.3 ± 0.3 μM. The cell density reduction was both a result of cell cycle arrest and apoptosis. The combination of PG and MF had a potentiated effect on cell density reduction, cell cycle arrest and apoptosis. The antiproliferative/cytotoxic effect of PG and MF in concentrations between 1 and 100 μM is of a non-genomic nature.