ENMD-1068, a protease-activated receptor 2 antagonist, inhibits the development of endometriosis in a mouse model.

Abstract

OBJECTIVE:

Protease-activated receptor 2 plays an important role in the pathogenesis of endometriosis. We studied the effect of ENMD-1068, a protease-activated receptor 2 antagonist, on the development of endometriosis in a noninvasive fluorescent mouse model.

STUDY DESIGN:

A red fluorescent protein-expressing xenograft model of human endometriosis was created in nude mice. After endometriosis induction, the mice were injected intraperitoneally with either 25 mg/kg or 50 mg/kg ENMD-1068 or with 200 μL of the vehicle control daily for 5 days. The endometriotic lesions that developed in the mice were then counted, measured, and collected. The lesions were assessed for the production of interleukin 6 and monocyte chemotactic protein-1 by enzyme-linked immunosorbent assays and evaluated for the activation of nuclear factor-κB and the expression of vascular endothelial growth factor by immunohistochemical analyses. Cell proliferation and apoptosis were assessed by immunohistochemistry for Ki-67 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, respectively.

RESULTS:

ENMD-1068 dose-dependently inhibited the development of endometriotic lesions (P < .05) without apparent toxicity to various organs of the treated mice. Consistently, ENMD-1068 dose-dependently inhibited the expression of interleukin 6 and nuclear factor-κB (P < .05) and cell proliferation (P < .05) in the lesions, as well as increased the percentage of apoptotic cells (P < .05). ENMD-1068 reduced the levels of monocyte chemotactic protein-1 and vascular endothelial growth factor in the lesions (P < .05), but not in a dose-dependent manner.

CONCLUSION:

Our study suggests that ENMD-1068 is effective in suppressing the growth of endometriosis, which might be attributed to the drug's antiangiogenic and antiinflammatory activities.

• Authors: Yifeng Wang, Min Lin, Huinan Weng, Xuefeng Wang, Li Yang, Fenghua Liu
• Journal: American journal of obstetrics and gynecology (Am J Obstet Gynecol) Vol. 210 Issue 6 Pg. 531.e1-8 (Jun 2014) ISSN: 1097-6868 [Electronic] United States
• PMID: 24495669 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Mosby, Inc. All rights reserved.

Chemical References

• 1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine
• Angiogenesis Inhibitors
• Chemokine CCL2
• Interleukin-6
• NF-kappa B
• Piperazines
• Receptor, PAR-2
• Vascular Endothelial Growth Factor A

Topics

• Angiogenesis Inhibitors (pharmacology, therapeutic use)
• Animals
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Chemokine CCL2 (analysis)
• Disease Models, Animal
• Endometriosis (drug therapy)
• Endometrium (drug effects, metabolism, pathology)
• Enzyme-Linked Immunosorbent Assay
• Female
• Immunohistochemistry
• Interleukin-6 (analysis)
• Mice
• Mice, Nude
• NF-kappa B (metabolism)
• Neovascularization, Pathologic (drug therapy, metabolism, pathology)
• Piperazines (pharmacology, therapeutic use)
• Receptor, PAR-2 (antagonists & inhibitors)
• Vascular Endothelial Growth Factor A (metabolism)