Suppressive Effects of Ursolic Acid on Human Endometriotic Stromal Cells Survival

Abstract

Background/Aims: The identification of new compound candidates for endometriosis treatment is needed. Cyclooxygenase-2 (COX-2) is considered a crucial target to control the progress and recurrence of endometriosis. Here, we identified ursolic acid (UA) as a natural inhibitor of COX-2 and investigated its effects on endometriosis progression. Methods: Primary human endometriotic stromal cells isolated from patients with endometriosis were exposed to UA at concentrations of 15, 30, 45, and 60 μM. 3-(4,5-Dimethylthiaziazol-2-yl)-2,5-diphenyl tetrazolium bromide assays, 5′-bromo-2’-deoxy-uridine assays, and Caspase-3 activity measurements were performed to detect cell growth and apoptosis. Enzyme-linked immunosorbent assays were used to detect COX-2 and vascular endothelial growth factor (VEGF) protein expression and prostaglandin E₂ (PGE₂) levels. Capillary-tubule formation assays using human umbilical vein endothelial cells were also carried out to determine angiogenesis. Results: UA significantly decreased cell viability, inhibited proliferation, and increased caspase-3 activity in a dose-dependent manner. COX-2 protein expression and the subsequent PGE₂ production were both reduced by UA. Meanwhile, UA exposure decreased VEGF secretion in the stromal cells and the capillary-tubule formation assay confirmed the inhibitory effect of UA on angiogenesis. Furthermore, UA increased the phosphorylation of c-Jun N-terminal kinase and p38. Conclusions: Our data suggest that UA plays a role as a natural inhibitor of COX-2 to control the survival of human endometriotic stromal cells by inhibiting proliferation and angiogenesis and promoting apoptosis.