Celecoxib inhibits proliferation of retinal pigment epithelial and choroid-retinal endothelial cells by a cyclooxygenase-2-independent mechanism

Abstract

Age-related macular degeneration (ARMD) is a leading cause of blindness. The major reason for severe vision loss in ARMD is choroidal neovascularization due to an elevation in the expression of angiogenic factors such as vascular endothelial growth factor (VEGF). Drugs with anti-VEGF and antiproliferative activities can be beneficial for the treatment of this disorder. We have previously demonstrated that celecoxib [a selective cyclooxygenase (Cox)-2 inhibitor] inhibits VEGF expression in retinal pigment epithelial cells. In this study, we investigated the antiproliferative effects of celecoxib in adult retinal pigment epithelial (ARPE-19) and choroidal endothelial (RF/6A) cells. The results indicate that celecoxib 1) causes a dose-dependent antiproliferative effect in ARPE-19 and RF/6A cells (IC(50) of 23 and 13 microM, respectively); 2) leads to a G(2)-M phase cell cycle arrest in these cell types; and 3) inhibits VEGF-induced proliferation of RF/6A cells (IC(50) of 20 microM). In addition, 4) the concentrations of celecoxib required for antiproliferative effects are lower than those required for the cytotoxicity. These effects of celecoxib are by mechanisms independent of its Cox-2 inhibitory activity because rofecoxib (another Cox-2 inhibitor) had no effects on the proliferation or cell cycle distribution of the two cell types, and flurbiprofen (an inhibitor of Cox-1 and Cox-2) had weak antiproliferative effects on ARPE-19 cells, with IC(50) of 90 microM. In summary, celecoxib has potent antiproliferative effects in RF/6A and ARPE-19 cells; thus, it can be a potential new treatment in proliferative disorders of the choroid-retina such as choroidal neovascularization in age-related macular degeneration.