Inhibition of proliferation of endometrial stromal cells by trichostatin A, RU486, CDB-2914, N-acetylcysteine, and ICI 182780.
BACKGROUND
All current major medications in treating endometriosis are effective in treating pain, most likely through suppression of proliferation of the implants, yet their effectiveness is relatively short term and they all have many undesirable, and sometimes severe, side effects. There is pressing need for novel, more effective medications in treating endometriosis with less and/or milder side effects.


METHODS
Using a recently established immortalized endometrial stromal cell line, we carried out cell proliferation assays for cells treated with trichostatin A (TSA), RU486, CDB-2914, and N-acetylcysteine, and ICI 182780. Gene expression levels for PR-A, PR-B, AR, Fas and FasL were measured. Protein expression levels for ERalpha, ERbeta, and AR were also measured.


RESULTS
Cell proliferation assay results for NAC, H2O2, CDB, and RU486 were nearly identical or similar to what have been reported based on primary cell cultures or in vivo studies. TSA, CDB, RU486 and NAC all had various antiproliferative effects. TSA had a more potent and longer lasting antiproliferative effect than CDB and NAC, even in the presence of an oxidant, H2O2. Its antiproliferative effect was concentration-dependent. ICI did not have a significant antiproliferative effect. PR-A, PR-B, AR, and FasL expression were all increased as compared with untreated cells.


CONCLUSIONS
The cell line appears to be an adequate model for stromal components of endometriotic implants. That ICI has no inhibitory effect on endometrial proliferation may explain why a phase II clinical trial on its use to treat endometriosis did not advance to later stages. The upregulation of PR-B and AR may be responsible for antiproliferative effects induced by TSA, a histone deacetylase inhibitor (HDACI). HDACIs may be promising therapeutics in treating endometriosis due to their antiproliferative effects as well as the potential to restore gene dysregulation through chromatin remodeling.
Wu
Yan
Y
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226-0509, USA.
Guo
Sun-Wei
SW
D000111:Acetylcysteine / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004715:Endometriosis / Q000188:drug therapy; D004717:Endometrium / Q000166:cytology / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D009649:Norpregnadienes / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism
D004791:Enzyme Inhibitors; C491901:FAS protein, human; D053222:Fas Ligand Protein; D006877:Hydroxamic Acids; D009649:Norpregnadienes; D012333:RNA, Messenger; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D019014:fas Receptor; D000077267:Fulvestrant; D015735:Mifepristone; C012589:trichostatin A; D004958:Estradiol; C094854:ulipristal; D006861:Hydrogen Peroxide; D000111:Acetylcysteine