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Application of the nuclear factor-κB inhibitor,BAY 11-7085,for the treatment of endometriosis

Yukie Kawano  Kaei Nasu  Masakazu Nishida  Wakana Abe  Hisashi Narahara  
【摘要】:Objectives:It has been demonstrated that endometrial apoptosis in the eutopic endometrium is lower in women with endometriosis than controls and is further decreased in the endometriotic lesions.Both the inability of endometriotic cells to transmit a 'death' signal and the ability of the cells to avoid cell death have been associated with increased expression of anti-apoptotic factors and the decreased expression of pre-apoptotic factors.One of the important functions of the pleiotropic transcription factor,nuclear factor(NF)-κB,is the ability to protect cells from apoptosis by activating anti-apoptotic genes.The constitutive activation of NF-κB has demonstrated in endometriotic cells,suggesting that NF-κB may play a significant role in the proliferation of endometriotic lesions.BAY 11-7085,a soluble inhibitor of NF-κB activation,has been shown to inhibit cell proliferation and induce apoptosis of a variety of cells.The aim of this study is to examine the potential application of BAY 11-7085 in the treatment of endometriosis.Materials and Methods:Primary cultures of endometriotic cyst stromal cells and normal endometrial stromal cells were utilized for the experiments.The cell proliferation of endometriotic cyst stromal cells and normal endometrial stromal cells after BAY 11-7085 treatment were determined by 5-bromo-2'-deoxyuridine incorporation assay.The BAY 11-7085-induced apoptosis of endometriotic cyst stromal cells and normal endometrial stromal cells was assessed by internucleosomal DNA fragmentation assays.The effect of BAY 11-7085 on the cell cycle of endometriotic cyst stromal cells was also determined by flow cytometry.The expression of apoptosis-related molecules was examined in endometriotic cyst stromal cells using Western blot analysis.Results:BAY 11-7085 significantly inhibited the cell proliferation of endometriotic cyst stromal cells and normal endometrial stromal cells.BAY 11-7085 showed a stronger inhibitory effect on the cell proliferation of endometriotic cyst stromal cells than on that of normal endometrial stromal cells.BAY 11-7085 significantly induced apoptosis of endometriotic cyst stromal cells and normal endometrial stromal cells.BAY 11-7085 showed a stronger stimulatory effect on the apoptosis of endometriotic cyst stromal cells than that of normal endometrial stromal cells.BAY 11-7085 significantly induced the G0/G1 phase cell cycle arrest of endometriotic cyst stromal cells.Additionally,down-regulation of B-cell lymphoma/leukemia-2(Bcl-2) and Bcl-XL expression was observed in endometriotic cyst stromal cells after treatment with BAY 11-7085.Conclusions:BAY 11-7085 may be applicable for the medical treatment of endometriosis as an adjuvant approach in combination with current medical treatment for this disease.BAY 11-7085 showed only weak effects on normal endometrial stromal cells in comparison with endometriotic cyst stromal cells,suggesting that BAY 11-7085 has cell-specific effects on endometriotic cyst stromal cells and its effects would be weaker on the normal endometrium.The control of inflammatory responses through NF-κB inactivation by BAY 11-7085 also seems to be a powerful therapeutic strategy for preventing pathological responses in endometriosis as a consequence of the enhanced release of inflammatory mediators.

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