SDF-1/CXCR4 signaling axis determines the proliferative potential and site-specific cancer metastasis. Recent studies suggest involvement of the axis and steroidal hormone in ovarian cancer metastasis. Here we hypothesize that mifepristone (RU486), a well-known progesterone-based abortifacient, might interfere this axis and inhibit ovarian cancer metastasis. Mifepristone at concentrations < IC50 inhibited expression of CXCR4 on cell surface of ovarian cancer SKOV-3 and IGROV-1, and reduced expression of the intracellular CXCR4 protein and its related mRNA activated by SDF-1. SDF-1 significantly stimulated proliferation of SKOV-3 and IGROV-1 cells with concomitant increases in intracellular phosphorylation of Akt and ERK. SDF-1 activated cell chemotatic migration and actin polymerization, and up-regulated expression of MMP-2, MMP-9, COX-2, VEGF without influencing the adhesion molecules ICAM-1 and integrins β1, α1, α3, α5, and α6. The above-mentioned effects of SDF-1 could be antagonized by mifepristone concentration-dependently, and CXCR4 antagonist AMD3100. Mifepristone suppressed the SDF-1-induced migration, invasion and adhesion of the cancer cells to extracellular matrixes. Three-day pretreatment of nude mice with mifepristone (5 and 20 mg/kg/day) followed by a single intraperitoneal IGROV-1 inoculation, along with repeated SDF-1 and mifepristone administrations in turn every other day for 36 days significantly reduced ascitic fluid, metastatic foci, tumor weight and immunoreactivity of CXCR4 in comparison with the SDF-1-treated control. Our results suggest that mifepristone inhibit SDF-1/CXCR4 signaling axis, may have preventive and therapeutic effects on ovarian cancer metastasis.

In addition to its well-known abortifacient effect, mifepristone (MIF) has been used as an anticancer drug for various cancers in many studies with an in-depth understanding of the mechanism of action. However, application of MIF is limited by its poor water solubility and low oral bioavailability. In this work, we developed a drug delivery system based on chitosan nanoparticles (CNs) to improve its bioavailability and anticancer activity. The MIF-loaded chitosan nanoparticles (MCNs) were prepared by convenient ionic gelation techniques between chitosan (Cs) and tripolyphosphate (TPP). The preparation conditions, including Cs concentration, TPP concentration, Cs/MIF mass ratio, and pH value of the TPP solution, were optimized to gain better encapsulation efficiency (EE) and drug loading capacity (DL). MCNs prepared with the optimum conditions resulted in spherical particles with an average size of 200 nm. FTIR and XRD spectra verified that MIF was successfully encapsulated in CNs. The EE and DL of MCNs determined by HPLC were 86.6% and 43.3%, respectively. The in vitro release kinetics demonstrated that MIF was released from CNs in a sustained-release manner. Compared with free MIF, MCNs demonstrated increased anticancer activity in several cancer cell lines. Pharmacokinetic studies in male rats that were orally administered MCNs showed a 3.2-fold increase in the area under the curve from 0 to 24 h compared with free MIF. These results demonstrated that MCNs could be developed as a potential delivery system for MIF to improve its anticancer activity and bioavailability.

Mifepristone (RU486), a synthetic steroid compound used as an abortifacient drug, has received considerable attention to its anticancer activity recently. To explore the possibility of using mifepristone as a cancer metastasis chemopreventive, we performed a systems pharmacology analysis of mifepristone-related molecules in the present study. Data were collected by using Natural Language Processing (NLP) and 513 mifepristone-related genes were dug out and classified functionally using a gene ontology (GO) hierarchy, followed by KEGG pathway enrichment analysis. Potential signal pathways and targets involved in cancer were obtained by integrative network analysis. Total thirty-three proteins were involved in focal adhesion-the key signaling pathway associated with cancer metastasis. Molecular and cellular assays further demonstrated that mifepristone had the ability to prevent breast cancer cells from migration and interfere with their adhesion to endothelial cells. Moreover, mifepristone inhibited the expression of focal adhesion kinase (FAK), paxillin, and the formation of FAK/Src/Paxillin complex, which are correlated with cell adhesion and migration. This study set a good example to identify chemotherapeutic potential seamlessly from systems pharmacology to cellular pharmacology, and the revealed hub genes may be the promising targets for cancer metastasis chemoprevention.

Recent scientific advances have increased our understanding of the cancer metastatic complexities and provided further impetus for new combination therapies to prevent cancer metastasis. Here, we demonstrated that a combination (HAMPT) of aspirin, lysine, mifepristone and doxycycline can effectively and safely prevent cancer metastasis. The pharmaceutically-formulated HAMPT inhibited adhesion of cancer cells to either endothelial cells or extracellular matrix via down-regulating cell adhesion molecules ICAM-1 and α4-integrin. HAMPT inhibited the cloak effect by activated platelets on cancer cells, thereby interfering adhesion and invasion of cancer cells to the underlying stroma. At the effective concentration, HAMPT induced cancer cells into dormancy with minor inhibition on cell viability. Four-day pretreatment followed by 30-day oral administration of HAMPT (33.5-134 mg/kg) to the mice inoculated with cancer cells produced significant inhibition on cancer metastasis dose-dependently without marked side effects. Fifty-day rat toxicity study with HAMPT at doses (335-1340 mg/kg) 20-fold higher than its therapeutic dose produced no significant toxicity. Interestingly, the acute toxic death could not be reached at the maximum administrable dose (5 g/kg). This proof-of-concept study provides the first conceptual evidence that cancer metastasis can be controlled by using affordable old drugs to restrain circulating tumor cells from gemmating on the metastatic soil without the need for cytotoxicity.

Mifepristone (RU486) is a chemical contraceptive marketed in more than 55 countries and used by hundreds of millions of women worldwide. Current studies reported its uses by both genders for a safe and long-term psychotic depression and particularly for traditional cancer chemotherapy. Here, we investigated the multidisciplinary data from recent large epidemiological chemoprevention studies for long-term use of oral contraceptives to reduce cancer risk, and from the unsuccessful clinical trials of mifepristone used as a post-metastatic anticancer drug, and elucidated the similarities and differences in cellular and molecular processes between embryonic implantation to endometrium and adhesion/invasion of circulating tumor cells (CTCs) to vascular endothelium. The deep analyses provide a stronger scientific basis for repurposing abortifacients for safe and effective cancer metastatic chemoprevention. Initiation of such cancer drug development strategy represents a paradigm shift from traditional post-metastasis treatments to novel pre-metastasis chemoprevention.

Metapristone is the primary metabolite of the abortifacient mifepristone (RU486), and is being developed as a safe and effective cancer metastatic chemopreventive agent for both sexes. Here, we systematically investigated the sex-related pharmacokinetics of metapristone in both rats and dogs, and explored the related mechanisms of actions. Administration of metapristone to rats and dogs showed that plasma concentrations of metapristone (AUC, C max ) were significantly higher in female dogs and rats than in males. The sex-related differences in pharmacokinetics become more significant after ten consecutive days of oral administration. Female liver microsomes metabolized metapristone significantly slower than the male ones. The results from P450 reaction phenotyping using recombinant cDNA-expressed human CYPs in conjunction with specific CYP inhibitors suggested that CYP1A2 and CYP3A4 are the predominant CYPs involved in the metapristone metabolism, which were further confirmed by the enhanced protein levels of CYP1A2 and CYP3A4 induced by 1-week oral administration of metapristone to rats. The highest tissue concentration of metapristone was found in the liver. The study demonstrates, for the first time, the sex-related pharmacokinetics of metapristone, and reveals that activities of liver microsomal CYP1A2 and CYP3A4 as well as the renal clearance are primarily responsible for the sex-related pharmacokinetics.

Metapristone is the most predominant biological active metabolite of mifepristone, and being developed as a novel cancer metastasis chemopreventive agent by us. Despite its prominent metastasis chemopreventive effect, the underlying mechanism remains elusive. Our study, for the first time, demonstrated that metapristone had the ability to prevent breast cancer cells from migration, invasion, and interfere with their adhesion to endothelial cells. To explore the underlying mechanism of metapristone, we employed the iTRAQ technique to assess the effect of metapristone on MDA-MB-231 cells. In total, 5,145 proteins were identified, of which, 311 proteins showed significant differences in metapristone-treated cells compared to the control group (P-value < 0.05). Bioinformatic analysis showed many differentially expressed proteins (DEPs) functionally associated with post-translational modification, chaperones, translation, transcription, replication, signal transduction, etc. Importantly, many of the DEPs, such as E-cadherin, vimentin, TGF-β receptor I/II, smad2/3, β-catenin, caveolin, and dystroglycan were associated with TGF-β and Wnt signaling pathways, which were also linked to epithelial-to-mesenchymal transition (EMT) process. Further validation of the epithelial marker "E-caderin" and mesenchymal marker "vimetin" were carried out using immunoblot and immunofluorescence. These results have revealed a novel mechanism that metapristone-mediated metastasis chemoprevention is through intervening the EMT-related signaling pathways.