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


METHODS
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.


CONCLUSIONS
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.
Department of Obstetrics and Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Yifeng
Y
Wang
Department of Obstetrics and Gynecology, Guangzhou Panyu Central Hospital, Guangzhou, China.
Min
M
Lin
Department of Reproductive Center, GuangDong Women And Children Hospital, Guangzhou, China.
Huinan
H
Weng
Department of Obstetrics and Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Xuefeng
X
Wang
Department of Obstetrics and Gynecology, Guangzhou Panyu Central Hospital, Guangzhou, China.
Li
L
Yang
Department of Reproductive Center, GuangDong Women And Children Hospital, Guangzhou, China. Electronic address: lfhsfy@163.com.
Fenghua
F
Liu
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000032:analysis; D004195:Disease Models, Animal; D004715:Endometriosis / Q000188:drug therapy*; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000032:analysis; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C518710:1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine; D020533:Angiogenesis Inhibitors; D018932:Chemokine CCL2; D015850:Interleukin-6; D016328:NF-kappa B; D010879:Piperazines; D044464:Receptor, PAR-2; D042461:Vascular Endothelial Growth Factor A
BABL/C mice; ENMD-1068; apoptosis; cell proliferation; endometriosis