Selective inhibition of 17beta-hydroxysteroid dehydrogenase type 1 (17betaHSD1) reduces estrogen responsive cell growth of T47-D breast cancer cells.
The most potent estrogen estradiol (E2) plays a pivotal role in the initiation and progression of estrogen dependent diseases. 17beta-Hydroxysteroid dehydrogenase type 1 (17betaHSD1) catalyses the NADPH-dependent E2-formation from estrone (E1). It is often overexpressed in breast cancer and endometriosis. For this reason, inhibition of 17betaHSD1 is a promising strategy for the treatment of these diseases. In the present paper, we investigate the estrogen responsive cell growth of T47-D breast cancer cells, the intracellular inhibitory activity of non-steroidal 17betaHSD1-inhibitors and their effects on estrogen dependent cell growth in vitro. At equal concentrations the estrogens E1 and E2 induced the same extent of growth stimulation indicating fast intracellular conversion of E1 into E2. Application of inhibitors selectively prevented stimulation of proliferation evoked by E1-treatment whereas E2-mediated stimulation was not affected. Furthermore, intracellular E2-formation from E1 was significantly inhibited with IC(50)-values in the nanomolar range. In conclusion, our findings strongly support suitability of non-steroidal 17betaHSD1-inhibitors for the treatment of estrogen dependent diseases.
8.2 Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
Patricia
P
Kruchten
Ruth
R
Werth
Emmanuel
E
Bey
Alexander
A
Oster
Sandrine
S
Marchais-Oberwinkler
Martin
M
Frotscher
Rolf W
RW
Hartmann
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004958:Estradiol / Q000494:pharmacology*; D004970:Estrone / Q000494:pharmacology; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D004970:Estrone; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase