AQ4, an antitumor anthracenedione, inhibits endothelial cell proliferation and vascular endothelial growth factor secretion: Implications for the therapy of ocular neovascular disorders

Current clinical options for the treatment of neovascular disorders of the posterior segment of the eye have several drawbacks. Photocoagulation lasers can impair peripheral and night vision. Photodynamic therapies as well as intravitreal macromolecule injections (Macugen® and Lucentis®) require frequent, invasive administrations. Above all, only modest improvement in vision is achieved with any of the existing treatments. In order to overcome these limitations in the long run, this study investigated the antiangiogenic potential of AQ4, a low molecular weight anthracenedione. The results indicate that AQ4 enters the cell nucleus and inhibits proliferation of choroid–retina endothelial (RF/6A) cells and human retinal pigment epithelial (ARPE-19) cells under hypoxic (1% O2) as well as normoxic (21% O2) conditions. The IC50 for these effects ranges from 5.5 to 6.9 μM. AQ4 does not affect the viability of non-dividing RF/6A or ARPE-19 cells up to 0.1 mM. Further, AQ4 (20 μM) reduces vascular endothelial growth factor (VEGF) protein secretion by about 50% in ARPE-19 cells under normoxia as well as hypoxia, possibly by reducing VEGF transcription. AQ4 arrests the growth of endothelial cells in S phase, consistent with interference of AQ4 with DNA replication. These results for the first time suggest that AQ4 can potentially alleviate the neovascularization of choroid/retina by a dual mechanism of inhibiting the proliferation of endothelial cells and by reducing mitogenic VEGF stimulus from retinal pigment epithelial cells.