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 proliferation and migration of retinal pigment epithelial (RPE) cells in the vitreous cavity. The drug hypericin, which is already in clinical use as an antidepressant, has shown promise as an antiviral and antineoplastic agent. To investigate the therapeutic potential of hypericin in PVR, we incubated RPE cells in standard medium with various serum concentrations containing 0.5 to 5 microM hypericin. In some experiments we studied the effects of hypericin in conjunction with the RPE growth stimulating cytokine tumor necrosis factor alpha (TNF-alpha). Dose-dependent inhibition of RPE cell proliferation with IC50 values of 0.7 microM and 3.3 microM in 1% and 5% serum respectively, was found. Even in conjunction with TNF-alpha, hypericin inhibited RPE proliferation with an IC50 value of 1.5 microM. The drug inhibited PKC activity in cells treated with a 2.5 microM dose by 72% after 30 min and by 100% after 180 min. Finally, hypericin induced RPE cells to undergo apoptotic cell death, as shown by the presence of DNA laddering. These results suggest that hypericin 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.
Harris
M S
MS
Doheny Eye Institute, Los Angeles, CA 90033, USA.
Sakamoto
T
T
Kimura
H
H
He
S
S
Spee
C
C
Gopalakrishna
R
R
Gundimeda
U
U
Yoo
J S
JS
Hinton
D R
DR
Ryan
S J
SJ
D000818:Animals; D000873:Anthracenes; D017209:Apoptosis / Q000187:drug effects*; D002273:Carcinogens / Q000378:metabolism; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000873:Anthracenes; D002273:Carcinogens; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D015240:Phorbol 12,13-Dibutyrate; D010569:Perylene; C004965:hypericin; D004247:DNA; D011493:Protein Kinase C