HYPERICIN INHIBITS CELL-GROWTH AND INDUCES APOPTOSIS IN RETINAL-PIGMENT EPITHELIAL-CELLS - POSSIBLE INVOLVEMENT OF PROTEIN-KINASE-C

Proliferative vitreoretinopathy (PVR) is characterized by the prolifer ation and migration of retinal pigment epithelial (RPE) cells in the v itreous cavity. The drug hypericin, which is already in clinical use a s an antidepressant, has shown promise as an antiviral and antineoplas tic agent. To investigate the therapeutic potential of hypericin in PV R, we incubated RPE cells in standard medium with various serum concen trations containing 0.5 to 5 mu M hypericin. In some experiments we st udied the effects of hypericin in conjunction with the RPE growth stim ulating cytokine tumor necrosis factor alpha (TNF-alpha). Dose-depende nt inhibition of RPE cell proliferation with IC50 values of 0.7 mu M a nd 3.3 mu M in 1% and 5% serum respectively, was found. Even in conjun ction with TNF-alpha, hypericin inhibited RPE proliferation with an IC 50 value of 1.5 mu M. The drug inhibited PKC activity in cells treated with a 2.5 mu M dose by 72% after 30 min and by 100% after 180 min. F inally, hypericin induced RPE cells to undergo apoptotic cell death, a s shown by the presence of DNA laddering. These results suggest that h ypericin may have potential as a therapeutic drug for PVR and that its antiproliferative and apoptotic effects on RPE cells in vitro are in part mediated by PKC.