Mifepristone (RU486): Progesterone Receptor Antagonist for Cancer and Reproductive Research

Executive Summary: Mifepristone (RU486) is a selective, high-affinity progesterone receptor antagonist supplied by APExBIO, utilized for modulating reproductive and cancer-related processes (APExBIO product page). It inhibits progesterone receptor activity, blocks hormone-driven proliferation in multiple cancer cell lines, and reduces uterine fibroid volume in validated models (Li et al., 2018). The compound demonstrates dose-dependent inhibition of ovarian cancer cell growth with IC50 values in the low micromolar range. Mifepristone's effects extend to suppression of the progesterone-induced acrosome reaction and cell cycle arrest via downregulation of cyclins. It is DMSO/ethanol-soluble, stable at -20°C, and validated in xenograft and in vitro protocols.

Biological Rationale

Mifepristone (RU486) functions as a competitive antagonist of the progesterone receptor (PR), a nuclear hormone receptor integral to reproductive tissue development, maintenance, and cancer cell proliferation (see related article). By inhibiting PR-mediated signaling, Mifepristone disrupts gene transcription programs essential for cell cycle progression in hormone-responsive tissues. Its high selectivity permits targeted modulation in both reproductive biology and oncology research workflows (SB-431542.com review).

This article extends previous guides by emphasizing quantitative benchmarks and clarifying the compound's validated workflow parameters, updating prior overviews with new mechanistic insights and application boundaries.

Mechanism of Action of Mifepristone (RU486)

Mifepristone binds to human progesterone receptors with high affinity (KD in nanomolar range), outcompeting endogenous progesterone and preventing receptor activation. This antagonism disrupts PR-driven gene expression, leading to inhibition of cellular proliferation and induction of cell cycle arrest in PR-positive tissues and tumors (APExBIO). Additionally, Mifepristone exhibits partial glucocorticoid receptor antagonist activity, which may influence downstream inflammatory and metabolic pathways in specific models (Li et al., 2018).

In vitro, Mifepristone suppresses the expression of S-phase (cyclin A) and M-phase (cyclin B1) cyclins, leading to cell cycle arrest. It also inhibits the progesterone-induced acrosome reaction, sperm hyperactivation, and intracellular calcium elevation in human sperm, demonstrating functional antagonism beyond female reproductive biology (Flunarizinelab.com).

Evidence & Benchmarks

• Mifepristone reduces uterine fibroid size in preclinical models under controlled dosing (Li et al., 2018, DOI:10.1038/s41467-018-06067-7).
• Demonstrates dose-dependent inhibition of ovarian cancer cell growth, with IC50 values of 6.25 μmol/L for SK-OV-3 and 6.91 μmol/L for OV2008 cell lines (APExBIO, product page).
• Inhibits cell proliferation in endometrial, breast, prostate, and gastric adenocarcinoma cell lines in vitro at concentrations ranging from 1–10 μmol/L (egf-receptor-substrate-eps15-acetyl.com).
• Suppresses progesterone-induced acrosome reaction, sperm hyperactivation, and calcium influx at 5–10 μmol/L in human sperm assays (Flunarizinelab.com).
• Reduces cyclin A and cyclin B1 expression in ovarian cancer cells, contributing to G1/S and G2/M cell cycle arrest (APExBIO, B1511 kit).
• Validated as a tool compound in xenograft models for dose-dependent tumor growth inhibition (Li et al., 2018, DOI).

For advanced workflows, see the Applied Workflows for Cancer and Reproductive Biology article, which offers protocol optimizations. This piece clarifies the molecular benchmarks and extends previously reported cell line data to validated in vivo endpoints.

Applications, Limits & Misconceptions

Mifepristone (RU486) is broadly applied in:

• Reproductive biology research (e.g., ovulation, fertilization, implantation, contraception models).
• Oncology studies, especially hormone-dependent tumor lines (prostate, endometrial, breast, ovarian, meningioma).
• Assays of hormone receptor signaling, including progesterone and glucocorticoid pathways.
• Cell cycle analysis via cyclin expression profiling.

Common Pitfalls or Misconceptions

• Mifepristone is not water-soluble; attempts to dissolve in aqueous buffers result in precipitation or loss of activity (use DMSO or ethanol, ≥21.48 mg/mL, gentle warming).
• It is not a pure glucocorticoid receptor antagonist and may have partial agonist effects in select contexts; always confirm receptor status in the tested system.
• Long-term storage of stock solutions above -20°C or repeated freeze-thaw cycles reduce potency; prepare aliquots and avoid extended storage in solution.
• Not all cancer cell lines are sensitive; efficacy is highest in PR-positive models (e.g., SK-OV-3, OV2008).
• Mifepristone is not suitable for in vivo studies targeting non-hormone-dependent tumors without prior validation.

For a deeper discussion of cell permeability and selectivity, the article at SB-431542.com provides a mechanistic framework. This current review updates the compound’s application range and clarifies storage/solubility boundaries.

Workflow Integration & Parameters

Mifepristone (RU486, B1511) from APExBIO is supplied as a solid, recommended to be stored at -20°C. Stock solutions in DMSO or ethanol are stable for several months below -20°C but should not be kept long-term. Shipping is on blue ice for small molecule stability. Experimental workflows validated with T47D (breast cancer, PR+) and A549 (lung cancer, GR+) cell lines for antagonist activity, with dose-response curves typically in the 1–10 μmol/L range. For tumor xenograft models, dose-dependent protocols demonstrate robust tumor growth inhibition (Li et al., 2018).

For researchers requiring in-depth protocol recommendations, see this workflow guide, which details troubleshooting and optimization steps not covered here.

Conclusion & Outlook

Mifepristone (RU486) remains a gold standard cell-permeable progesterone receptor antagonist for cancer and reproductive research. Its high selectivity, reproducible anti-proliferative effects, and compatibility with established workflows make it indispensable for mechanistic and translational studies. Ongoing research explores its application in combinatorial regimens and emerging tumor models, with future directions targeting additional hormone-dependent disease pathways. For detailed product specifications and ordering, refer to the APExBIO Mifepristone (RU486) B1511 kit page.