gsk343 and Endometriosis

Endometriosis is a painful gynecological disease with no cure and limited therapeutic options. It has been hypothesized that epigenetic drugs can be used as a nonhormonal treatment for endometriosis. This study was conducted to study the efficacy of an inhibitor of the histone methyltransferase EZH2 using an established rat model of endometriosis. We hypothesized that treatment will block or reduce the number of endometriotic vesicles in this model. We conducted a preclinical drug study in female rats with experimental endometriosis (uterine tissue transplanted next to the intestinal mesentery) or control sham (sutures only). Rats with endometriosis or sham surgery received either treatment with EZH2 inhibitor (5 mg/kg or 10 mg/kg) or vehicle (0.1%, 67% DMSO) every other day during 4 weeks. After treatment completion, the number, area, volume, and weight of vesicles were evaluated. RT [2] Profiler Arrays for neuropathic and inflammation, epithelial to mesenchymal transition, inflammatory response, and autoimmunity pathways were used to examine gene expression changes in the vesicles that developed. Treatment with EZH2 inhibitor (10 mg/kg) suppressed the development of vesicles, by significantly decreasing the total vesicle number, area, volume, and weight. In addition, EZH2 inhibition significantly increased the expression of CACNA1B and FKBP1A genes, involved in pain and proliferation, respectively. EZH2 inhibition suppresses the growth of vesicles without apparent detrimental effects to other organs. Treatment with this epigenetic inhibitor leads to upregulation of a limited number of genes related to endometriosis-relevant pathways. In conclusion, these data support follow-up studies to evaluate its potential as a therapeutic approach for endometriosis.

Topics: Animals; Disease Models, Animal; Endometriosis; Endometrium; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Female; Indazoles; Pyridones; Rats; Rats, Sprague-Dawley

Although the histone methyltransferase EZH2 and its product H3K27me3 are well studied in cancer, little is known about their role and potential as therapeutic targets in endometriosis. We have previously reported that endometriotic lesions are characterized by global enrichment of H3K27me3. Therefore, we aimed to (1) characterize the expression levels of EZH2 in endometriotic tissues; (2) assess H3K27me3 enrichment in candidate genes promoter regions; and (3) determine if pharmacological inhibition of EZH2 impacts migration, proliferation, and invasion of endometriotic cells. Immunohistochemistry of an endometriosis-focused tissue microarray was used to assess the EZH2 protein levels in tissues. Chromatin immunoprecipitation-qPCR was conducted to assess enrichment of H3K27me3 in candidate gene promoter regions in tissues. Immunofluorescence was performed to assess the effect of an EZH2-specific pharmacological inhibitor on H3K27me3 global enrichment in cell lines. To measure effects of the inhibitor in migration, proliferation, and invasion in vitro we used Scratch, BrdU, and Matrigel assays, respectively. Endometriotic lesions had significantly higher EZH2α nuclear immunostaining levels compared to eutopic endometrium from patients (glands, stroma) and controls (glands). H3K27me3 was enriched within promoter regions of candidate genes in some but not all of the endometriotic lesions. Inhibition of EZH2 reduced H3K27me3 levels in the endometriotic cells specifically, and also reduced migration, proliferation but not invasion of endometriotic epithelial cells (12Z). These findings support future preclinical studies to determine in vivo efficacy of EZH2 inhibitors as promising nonhormonal treatments for endometriosis, still an incurable gynecological disease.

Topics: Adult; Cell Line; Cell Movement; Cell Proliferation; Endometriosis; Endometrium; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Female; Humans; Indazoles; Middle Aged; Pyridones