COX-2 and PPARgamma as alternative targets for endometriosis.

OLIVARES C; RICCI A; BILOTAS M; BARAÑAO RI; MERESMAN G

Montpellier

Congreso; 11th World Endometriosis Congress; 2011

World Endometriosis Society

The pursue for new treatment options for endometriosis patients is constant. Previous reports demonstrated that inhibiting cyclooxygenase (COX)-2 and activating peroxisome proliferator-activated receptor (PPAR)γ has antiproliferative, proapoptotic and antiangiogenic effects in different in vivo and in vitro cancer models. Objectives: Study the effect of the inhibition of COX-2 and/or the activation of PPARγ on the development of endometriotic like lesions in a murine model. Methods: Two months old BALB/c mice were surgically induced with endometriosis. After 28 days of daily treatment with vehicle (100µl), celecoxib (200mg/kg), rosiglitazone (0.16mg/kg) or their combination, animals were sacrificed; developed lesions were counted, measured, excised and fixed in formalin. All treatments were administered by esophageal gavage. Paraffin embedded specimens were cut into 5µm sections for posterior apoptosis determination by TdT-mediated dUTP Nick-End Labeling (TUNEL) technique, cellular proliferation rate by immunohistochemistry of the proliferation cell nuclear antigen (PCNA) and vascularized area determination performing CD31 and CD34 immunohistochemistry. Results: The number of developed lesions was significantly reduced by celecoxib and the combined treatment (p<0.05 all groups vs. vehicle), whereas all treatment groups had diminished lesion volume (p<0.05 celecoxib and rosiglitazone separately vs. vehicle; p<0.001 combined treatment vs. vehicle). When PCNA positive cells were analyzed, it was found that all three treatments were successful at reducing cell proliferation within the lesions (p<0.01 celecoxib vs. vehicle; p<0.001 rosiglitazone and combined treatment vs. vehicle). Consistent with this result, apoptosis levels were found to be significantly enhanced by all treatments (p<0.05 all groups vs. vehicle). Furthermore, the vascularized area within the lesion was significantly reduced by all treatments (CD31: p<0.05 rosiglitazone and combined treatment vs. vehicle; CD34: p<0.05 celecoxib and rosiglitazone separately vs. vehicle; p<0.01 combined treatment vs. vehicle). Conclusions: In the present study, we found that celecoxib and rosiglitazone treatments, combined or separately, inhibited endometriotic-like lesion establishment and growth. To clarify the mechanism by which these drugs inhibit the growth of the implants, cell proliferation, apoptosis and vascular density were assessed. After treatment administration, we have seen markedly decreased proliferation and augmented apoptosis when lesions were examined. These indexes, together with the decreased vascularized area, must be responsibles for the decreased number of developed lesions observed. Nevertheless, we have still to elucidate the molecular pathways implicated in the effects seen. The results obtained are promising and encourage us to continue our research for being able to assess in full if the molecules proposed are feasible of being targeted for the treatment of endometriosis in the future.