onapristone and Endometrial-Neoplasms

Antiprogestogens, which block the action of progesterone at the cellular level through binding to the progesterone receptor, are proving to be one of the most significant developments in endocrinology in recent years. Several hundreds of such compounds have been synthesized, but only a few of them have been evaluated to any significant extent in biological screening models and, to our knowledge, only three compounds, namely mifepristone, lilopristone (ZK 98.734) and onapristone (ZK 98.299) have been given to humans. Most of the clinical research to date has focused on the use of mifepristone given in combination with prostaglandin for termination of early pregnancy, an indication for which the compound is being used routinely in four countries so far, i.e. China, France, the UK and Sweden. The gynaecological and obstetrical applications in which antiprogestogens have been shown to be of value to date include ripening of the pregnant cervix prior to pregnancy termination, sensitization of the uterus to prostaglandins in second-trimester abortion, and induction of labour. Available data suggest that antiprogestogens have no place in the conservative treatment of ectopic pregnancy or in the treatment of premenstrual tension. In fertility regulation, the sequential combination regimen of mifepristone plus prostaglandin as used for inducing abortion has proved to be effective also for menses induction and can be expected to be an efficacious once-a-month contraceptive. Mifepristone alone, without adjuvant prostaglandin, has yielded promising results as an anti-implantation agent and in emergency contraception. Other potential uses include once-a-week contraception, ovulation inhibition (in a sequential regimen with a progestogen), and as a daily mini-pill. Mifepristone, and other antiprogestogens for which biological data have been reported also bind to the cellular receptors for glucocorticoid hormones and, consequently, possess antiglucocorticoid in addition to their antiprogestational activity. Because of this antiglucocorticoid effect, mifepristone has been employed successfully in the palliative treatment of hypercortisolism due to Cushing's syndrome, and its use has been proposed for treating certain forms of depression and of glaucoma, and in wound healing. However, for scientific and practical reasons, it would be preferable if molecules were developed that have only the antiprogestational or the antiglucocorticoid activity rather than both.

Topics: Abortion, Induced; Antineoplastic Agents; Breast Neoplasms; Contraception; Contraceptives, Oral, Synthetic; Endometrial Neoplasms; Endometriosis; Estrenes; Female; Gonanes; Humans; Labor, Induced; Mifepristone; Pregnancy; Pregnancy Trimester, Second; Progestins; Prostaglandins; Receptors, Progesterone

Progesterone receptor (PR) isoforms (PRA and PRB) are implicated in the progression of breast cancers frequently associated with imbalanced PRA/PRB expression ratio. Antiprogestins represent potential antitumorigenic agents for such hormone-dependent cancers. To investigate the mechanism(s) controlling PR isoforms degradation/stability in the context of agonist and antagonist ligands, we used endometrial and mammary cancer cells stably expressing PRA and/or PRB. We found that the antiprogestin RU486 inhibited the agonist-induced turnover of PR isoforms through active mechanism(s) involving distinct MAPK-dependent phosphorylations. p42/44 MAPK activity inhibited proteasome-mediated degradation of RU486-bound PRB but not PRA in both cell lines. Ligand-induced PRB turnover required neosynthesis of a mandatory down-regulating partner whose interaction/function is negatively controlled by p42/44 MAPK. Such regulation strongly influenced expression of various endogenous PRB target genes in a selective manner, supporting functional relevance of the mechanism. Interestingly, in contrast to PRB, PRA stability was specifically increased by MAPK kinase kinase 1-induced p38 MAPK activation. Selective inhibition of p42/p44 or p38 activity resulted in opposite variations of the PRA/PRB expression ratio. Moreover, MAPK-dependent PR isoforms stability was independent of PR serine-294 phosphorylation previously proposed as a major sensor of PR down-regulation. In sum, we demonstrate that MAPK-mediated cell signaling differentially controls PRA/PRB expression ratio at posttranslational level through ligand-sensitive processes. Imbalance in PRA/PRB ratio frequently associated with carcinogenesis might be a direct consequence of disorders in MAPK signaling that might switch cellular responses to hormonal stimuli and contribute towards pathogenesis.

Topics: Breast Neoplasms; Cell Line, Tumor; Endometrial Neoplasms; Female; Gonanes; Humans; Ligands; MAP Kinase Kinase Kinase 1; Mifepristone; Mitogen-Activated Protein Kinase 1; Models, Biological; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Phosphoserine; Promegestone; Proteasome Endopeptidase Complex; Protein Isoforms; Protein Stability; Receptors, Progesterone; Transcription, Genetic

Estrogenic activities of testosterone (T) and 5a-dihydrotestosterone (DHT) were detected and measured by using their specific stimulatory effects on alkaline phosphatase (AP) activity in human endometrial adenocarcinoma cells of the Ishikawa Var-1 line. These two physiologic androgens were able to induce, at microM concentrations, estrogenic effect believed to be mediated by the estrogen receptor (ER) since the antiestrogens ICI-164384 and 4-hydroxytamoxifen (OHTam), but not the antiandrogens hydroxyflutamide (OHFl) or cyproterone acetate (CPA), reversed that effect. By using another in vitro bioassay, based on the progestin-specific stimulation of AP activity in cells of the T47D human breast cancer line, progestagenic activity was detected and measured in T, DHT and three synthetic androgens: nandrolone (19-nortestosterone). 7 alpha-methyl 19-nortestosterone (MENT) and mibolerone (7 alpha, 17 alpha-dimethyl 19-nortestosterone) (DMNT). While progestagenic effects of T and DHT required relatively high concentrations (microM levels), the synthetic androgens stimulated AP activity at nM or pM levels. These effects seem to be mediated by the progesterone receptor (PR), since they are completely abolished by the antiprogestins RU-486, ZK-98299 and ZK-112993, but not by the antiandrogen OHFl. These simple in vitro bioassays, expressing biological effects of the test compounds in human cells in culture, revealed dual or multiple hormonal activities coexisting in a single compound and provide quantitative information of considerable pharmacological importance concerning the complex actions of drugs.

Topics: Adenocarcinoma; Alkaline Phosphatase; Androgen Antagonists; Androgens; Breast Neoplasms; Cyproterone Acetate; Endometrial Neoplasms; Estradiol; Estrogen Antagonists; Female; Flutamide; Gonanes; Humans; Mifepristone; Polyunsaturated Alkamides; Progestins; Tamoxifen; Testosterone; Testosterone Congeners; Tumor Cells, Cultured