Yan Wu1, Sun-Wei Guo. 1. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226-0509, USA.
Abstract
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. Copyright 2006 S. Karger AG, Basel.
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. Copyright 2006 S. Karger AG, Basel.
Authors: Peter A W Rogers; G David Adamson; Moamar Al-Jefout; Christian M Becker; Thomas M D'Hooghe; Gerard A J Dunselman; Asgerally Fazleabas; Linda C Giudice; Andrew W Horne; M Louise Hull; Lone Hummelshoj; Stacey A Missmer; Grant W Montgomery; Pamela Stratton; Robert N Taylor; Luk Rombauts; Philippa T Saunders; Katy Vincent; Krina T Zondervan Journal: Reprod Sci Date: 2016-09-27 Impact factor: 3.060
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