Department of Basic Sciences, Ponce Research Institute, Ponce Health Sciences University, PO BOX 7004, Ponce, PR, 00732, Puerto Rico.
St. Luke's Episcopal Hospital, Ponce, PR, Puerto Rico.
Reprod Sci. 2020 Sep;27(9):1812-1820. doi: 10.1007/s43032-020-00257-9. Epub 2020 Jul 10.
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.
子宫内膜异位症是一种无法治愈且治疗选择有限的疼痛性妇科疾病。有人假设表观遗传药物可用作子宫内膜异位症的非激素治疗方法。本研究旨在使用已建立的子宫内膜异位症大鼠模型来研究组蛋白甲基转移酶 EZH2 抑制剂的疗效。我们假设治疗将阻止或减少该模型中子宫内膜异位症囊泡的数量。我们对患有实验性子宫内膜异位症（子宫组织移植到肠系膜旁）或对照假手术（仅缝线）的雌性大鼠进行了临床前药物研究。患有子宫内膜异位症或假手术的大鼠每隔一天接受 EZH2 抑制剂（5mg/kg 或 10mg/kg）或载体（0.1%、67% DMSO）治疗，持续 4 周。治疗完成后，评估囊泡的数量、面积、体积和重量。用于神经病变和炎症、上皮间质转化、炎症反应和自身免疫途径的 RT [2] Profiler Arrays 用于检查形成的囊泡中的基因表达变化。EZH2 抑制剂（10mg/kg）治疗抑制了囊泡的发育，显著减少了总囊泡数量、面积、体积和重量。此外，EZH2 抑制显著增加了 CACNA1B 和 FKBP1A 基因的表达，分别涉及疼痛和增殖。EZH2 抑制抑制囊泡的生长，而对其他器官没有明显的不利影响。用这种表观遗传抑制剂治疗会导致与子宫内膜异位症相关途径相关的少数基因上调。总之，这些数据支持进一步研究，以评估其作为子宫内膜异位症治疗方法的潜力。
