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

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• 作者：Yifeng Wang ; MD^a ; Min Lin ; MD^b ; Huinan Weng ; MD^c ; Xuefeng Wang ; MD^a ; Li Yang ; MD^b ; Fenghua Liu ; MD^c ; ^{lfhsfy@163.com" class="auth_mail}
• 关键词：apoptosis ; BABL/C mice ; cell proliferation ; endometriosis ; ENMD-1068
• 刊名：American Journal of Obstetrics and Gynecology
• 出版年：June 2014
• 年：2014
• 卷：210
• 期：6
• 页码：531.e1-531.e8
• 全文大小：2095 K

文摘

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 渭L 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-魏B 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-魏B (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.