Received for publication July 20, 2007.
Revised November 19, 2007.
Accepted for publication November 20, 2007.

Celecoxib inhibits VEGF induced proliferation of choroid-retinal endothelial cells by a Cox-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 anti-proliferative activities can be beneficial for the treatment of this disorder. We have previously demonstrated that celecoxib (a selective cyclooxygenase-2 (Cox-2) inhibitor) inhibits vascular endothelial growth factor (VEGF) expression in retinal pigment epithelial cells. In this study, we investigated the anti-proliferative effects of celecoxib in retinal pigment epithelial (ARPE-19) and choroidal endothelial cells (RF/6A). The results indicate that celecoxib: 1) causes a dose dependent anti-proliferative effect in ARPE-19 and RF/6A cells with IC₅₀ of 23 and 13 µM, respectively; 2) leads to a G2-M phase cell cycle arrest in these cell types 3) inhibits VEGF induced proliferation of RF/6A cells with an IC₅₀ of 20 µM; and 4) the concentrations of celecoxib required for anti-proliferative effects are lower than those required for the cytotoxicity. These effects of celecoxib are by mechanisms independent of its Cox-2 inhibitory activity as 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 anti-proliferative effects on ARPE-19 cells with IC₅₀ of 90 µM. In summary, celecoxib has potent anti-proliferative effects in RF/6A and ARPE-19 cells and thus can be a potential new treatment in proliferative disorders of the choroid-retina such as choroidal neovascularization in age related macular degeneration.

Key words: anti-proliferative, celecoxib, cell cycle, choroidal neovascularization, flurbiprfofen, rofecoxib