Hum. Reprod. Advance Access published online on August 20, 2008
Human Reproduction, doi:10.1093/humrep/den315
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Effects of a selective cyclooxygenase-2 inhibitor on endometrial epithelial cells from patients with endometriosis
1 Instituto de Biología y Medicina Experimental (IBYME-CONICET), Vuelta de Obligado 2490 (C1428ADN), Ciudad Autónoma de Buenos Aires, Argentina 2 Hospital de Clínicas Jose de San Martín, Av. Córdoba 2351 (C1120AAR), Ciudad Autónoma de Buenos Aires, Argentina 3 Centro de Ginecología y Reproducción (CEGYR), Viamonte 1432 (C1055ABB), Ciudad Autónoma de Buenos Aires, Argentina
4 Correspondence address. Tel: +54-11-47832869; Fax: +54-11-47862564; E-mail: meresman{at}dna.uba.ar
BACKGROUND: Celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, also has anti-proliferative properties and pro-apoptotic effects on different in vivo and in vitro models, two actions that may be efficacious in therapy for endometriosis. We evaluated the effects of celecoxib on apoptosis and proliferation, and vascular endothelial growth factor (VEGF) production and COX-2 expression and activity in endometrial epithelial cells (EECs).
METHODS AND RESULTS: Thirty-two endometriosis and 13 control women were included in the study. EECs from eutopic endometrium and control biopsies were cultured with different doses of celecoxib. Celecoxib at 50, 75 and 100 µM (versus vehicle control) inhibited EEC proliferation in cultures from controls (P < 0.05, P < 0.01 and P < 0.01, respectively) and patients with endometriosis (P < 0.05, P < 0.01 and P < 0.01), as assessed by 3H-thymidine uptake. Celecoxib at 50, 75 and 100 µM induced apoptosis in EEC from controls (P < 0.05, P < 0.001 and P < 0.001) and patients with endometriosis (P < 0.001, P < 0.001 and P < 0.01), as revealed by the Acridine Orange–Ethidium Bromide technique. Western blot analysis showed that celecoxib was effective at increasing COX-2 protein at 100 µM in EEC from endometriosis patients (P < 0.05). In EEC from endometriosis patients, celecoxib at 25, 50 and 100 µM was also effective in reducing COX-2 activity, reflected in the reduction of prostaglandin E2 (PGE2) synthesis (P < 0.001), and VEGF secretion (P < 0.001; P < 0.05 and P < 0.001), assessed by enzyme-linked immunosorbent assay. Exogenous PGE2 did not reverse celecoxib-induced growth inhibition.
CONCLUSIONS: This study suggests a direct effect of celecoxib on reduction of endometrial growth and supports further research on selective COX-2 inhibition as a novel therapeutic modality in endometriosis.
Key words: endometriosis/cyclooxygenase-2 inhibitor/eutopic endometrium/apoptosis/cell proliferation
Submitted on April 25, 2008; resubmitted on July 16, 2008; accepted on July 21, 2008.
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