Synthesis and Biological Activity of a Novel, Highly Potent Progesterone Receptor Antagonist

Fuhrmann, Ulrike; Hess‐Stumpp, Holger; Cleve, Arwed; Neef, Günter; Schwede, Wolfgang; Hoffmann, Jens; Fritzemeier, Karl-Heinrich; Chwalisż, Kristof

doi:10.1021/jm001000c

Cited by 93 publications

(65 citation statements)

References 31 publications

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“…This discrepancy suggested the possibly important role of iNOS in the development of chorionic villi during early gestation. In rodents, Saxena et al reported up-regulation of iNOS in implantation site [46] and Fuhrmann et al demonstrated the importance of the combination of iNOS and progesterone in implantation [47]. By contrast, Ariel et al identified eNOS immunoreactiviry in the human extravillous trophoblastic cells, suggesting the possible involvement of eNOS in human implantation [48].…”

Section: Discussionmentioning

confidence: 99%

Expression of Nitric Oxide Synthase Isoforms in the Human Placenta Is Not Altered by Labor

et al. 2003

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Abstract. Nitric oxide has various biological activities including smooth muscle relaxation, anti-inflammatory activity, anti-coagulatory activity. As the human placenta is known to express nitric oxide synthases, this study investigated the possible effect of labor on the expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) in human placental tissues at term. Both eNOS and iNOS mRNA expression in placental tissues in labor were significantly higher than those in the amnion, chorion laeve, decidua vera and myometrium. The eNOS mRNA and protein expressions in placental tissues in labor (n = 12) were 1.6023 ± 0.1652 (eNOS/GAPDH, mean ± SEM) and 12.8 ± 1.3 arbitrary units (AU), respectively, which were similar to those not in labor (n = 10), 1.5806 ± 0.2042 (eNOS/GAPDH) and 11.4 ± 1.8 AU. The iNOS mRNA and protein expressions in the placental tissues in labor were 1.2831 ± 0.2436 (iNOS/GAPDH) and 10.7 ± 2.1 AU respectively, similar to those not in labor, 1.9254 ± 0.8004 (iNOS/GAPDH) and 13.3 ± 1.8 AU. The guanosine 3',5'-cyclic monophosphate (cGMP) cocentration in the placental tissues in labor was 23.6 ± 1.4 fmol/g wet tissue, similar to that not in labor, 26.1 ± 2.0 fmol/g wet tissue. These findings suggest that nitric oxide production in the human placenta is maintained during labor.

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Section: Discussionmentioning

confidence: 99%

Expression of Nitric Oxide Synthase Isoforms in the Human Placenta Is Not Altered by Labor

et al. 2003

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“…It is also interesting to note that the functions of progesterone and RU486 can be differentially mediated by two PR isoforms that arise from the same gene and function to exhibit different transcription regulatory activities in vitro and in vivo (Conneely et al, 2001;Fuhrmann et al, 2000). In the presence of cAMP, RU486 can exhibit inappropriate gene activation in T47D subline expressing PR isoform B but not in cells expressing isoform A (Sartovius et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Demonstration of mixed properties of RU486 in progesterone receptor (PR)-transfected MDA-MB-231 cells: a model for studying the functions of progesterone analogues

Lin

et al. 2001

Br J Cancer

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Summary Progesterone antagonist RU486 (mifepristone) has been implicated for many anti-neoplastic and obstetrical applications. But the compound has demonstrated undesired agonist-like effect depending on cell, tissue and species studied. Using PR-transfected breast cancer cells MDA-MB-231, this report describes the similarities and differences between progesterone-and RU486-mediated effects on cell growth, cell differentiation and, at the molecular level, on the activation of p44/p42 MAP kinases (MAPK). Like progesterone, RU486 inhibited cells growth by arresting the cells in G0/G1 phase of the cell cycle. In contrast to progesterone that induced cell spreading, RU486 induced a multipolar, stellate morphology. RU486-treated cells showed no increase of stress fibers, nor was there any increase of focal adhesions as progesterone-treated cells did. Furthermore, despite of the fact that both compounds inhibited cell growth, RU486 significantly stimulated the activation of p44/p42 MAP kinases whereas progesterone markedly inhibited the activation. Nonetheless, the effects of RU486 were PR-mediated and RU486 was able to antagonize the effect of progesterone on cell growth and focal adhesion. In conclusion, RU486 can act not only as a progesterone antagonist, a progesterone agonist but also induced morphological and molecular changes that were distinct from progesterone-mediated effects in PR-transfected MDA-MB-231 cells. The non-progesterone-like effect of RU486 may be mediated through a pathway that is different from the progesterone-mediated pathway, or it is the result of a blockade of certain critical step(s) in the progesterone-mediated pathway. MATERIALS AND METHODS ChemicalsProgesterone was obtained from Sigma Chemical Co (St. Louis, MO USA). RU486 (mifepristone) and ZK98299 (onapristone) were from Siniwest Holdings, Inc. All tissue culture plastics and reagents were obtained from GIBCO BRL, Life Technologies, Inc. Cell cultureMDA-MB-231 cells were obtained from American Tissue Culture Collection (ATCC) in 1995 at passage 28. MDA-MB-231 cells were cloned using 96-well plates by plating 0.5 cell/well. Clone 2 (known as MDA-MB-231-CL2) was selected for transfection studies. All cells were routinely maintained in phenol-red containing Dulbecco's Modified Eagle Medium (DMEM) supplemented with 7.5% fetal calf serum (FCS), 2 mM glutamine and 40 mg/l gentamycin. TransfectionMDA-MB-231-CL2 cells were transfected with PR expression vectors hPR1 and hPR2 coding for PR isoform B and isoform A, respectively, in pSG5 plasmid (Kastner et al, 1990). Vector pBK-CMV (Stratagene) containing the neomycin-resistant gene was cotransfected with hPR1 and hPR2. Details of transfection were described previously (Lin et al, 1999). Cell growthCells (2 × 10 4 ) in their late exponential growth phase were seeded onto the 6-well plates in phenol red-free DMEM supplemented with 2 mM L-glutamine, 40 mg/l gentamycin and 5% dextran-coated charcoal (DCC)-treated FCS (Test Medium). Treatment of FCS with dextran-coated charcoal was to remove fro...

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“…mice so far (Banaszak et al, 2000;Fuhrmann et al, 2000;Sanchez-Criado et al, 2000;Xu et al, 2000;Slayden et al, 2001) . We selected two doses of ZK (6 and 9 mg/kg) based on previous studies in rats (Xu et al, 2000;Sanchez-Craido et al, 2000).…”

Section: Determine Whether Zk Blocks Lordosis Behavior and Y1r Expresmentioning

confidence: 95%

“…neonatally (P0-P10) for the males and prepubertally (P15-P25) for the females. RU486 has been criticized for its use as selective PR antagonist since it is known to interfere with glucocorticoid receptors, which is not the case for ZK137316 (Banaszak et al, 2000;Fuhrmann et al, 2000;Sanchez-Criado et al, 2000;Xu et al, 2000;Slayden et al, 2001). …”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Potential contribution of progesterone receptors to the development of sexual behavior in male and female mice

Desroziers

Brock

Bakker

2017

Hormones and Behavior

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We previously showed that estradiol can have both defeminizing and feminizing effects on the developing mouse brain. Pre-and early postnatal estradiol defeminized the ability to show lordosis in adulthood, whereas prepubertal estradiol feminized this ability. Furthermore, we found that estradiol upregulates progesterone receptors (PR) during development, inducing both a male-and female-typical pattern of PR expression in the mouse hypothalamus. In the present study, we took advantage of a newly developed PR antagonist (ZK 137316) to determine whether PR contributes to either male-or female-typical sexual differentiation. Thus groups of male and female C57Bl/6j mice were treated with ZK 137316 or oil as control: males were treated neonatally (P0-P10), during the critical period for male sexual differentiation, and females were treated prepubertally (P15-P25), during the critical period for female sexual differentiation. In adulthood, mice were tested for sexual behavior. In males, some minor effects of neonatal ZK treatment on sexual behavior were observed: latencies to the first mount, intromission and ejaculation were decreased in neonatally ZK treated males; however, this effect disappeared by the second mating test. By contrast, female mice treated with ZK during the prepubertal period showed significantly less lordosis than OIL-treated females. Mate preferences were not affected in either males or females treated with ZK during development. Taken together, these results suggest a role for PR and thus perhaps progesterone in the development of lordosis behavior in female mice. By contrast, no obvious role for PR can be discerned in the development of male sexual behavior.

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Synthesis and Biological Activity of a Novel, Highly Potent Progesterone Receptor Antagonist

Cited by 93 publications

References 31 publications

Expression of Nitric Oxide Synthase Isoforms in the Human Placenta Is Not Altered by Labor

Expression of Nitric Oxide Synthase Isoforms in the Human Placenta Is Not Altered by Labor

Demonstration of mixed properties of RU486 in progesterone receptor (PR)-transfected MDA-MB-231 cells: a model for studying the functions of progesterone analogues

Potential contribution of progesterone receptors to the development of sexual behavior in male and female mice

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