Table 1.
Evidence linking APE1/Ref-1 inhibitors with eye disease. Redox inhibitors APX3330, APX2009 and APX2014 have been assessed in multiple systems. For structures of compounds mentioned, refer to Figure 1. Abbreviations: RVECs, retinal vascular endothelial cells; ARPE-19, adult retinal pigment epithelium-19 cell line; CI, cell index; MCP-1, monocyte chemoattractant protein-1; oxLDL, oxidized low density lipoprotein; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor; NF-κB, Nuclear factor κ light-chain-enhancer of activated B cells; Nrf2/Nrf1, Nuclear factor erythroid 2-related factor 2 and 1; HIF-1, hypoxia-inducible factor 1; CBF/NF-Y, CCAAT-binding factor; YY1, Ying yang-1; MTF1, metal regulatory transcription factor 1; HSF-1, heat shock factor 1; Rf-6a, macaque choroidal endothelial cell-like cell line; STAT3, signal transducer and activator of transcription 3; HRECs, human retinal microvascular endothelial cells; VCAM1, vascular cell adhesion molecule 1; CCL20, C-C motif chemokine ligand 20; VEGFA, vascular endothelial growth factor A; TUNEL, Terminal deoxynucleotidyl transferase dUTP nick end labeling; IVT, intravitreal; L-CNV, laser-induced choroidal neovascularization; IP, intraperitoneal.
| Intervention | System | Findings | Reference |
|---|---|---|---|
| In vitro | |||
| APX3330 | RVECs | Dose-dependently suppressed proliferation, migration and tube formation | [30] |
| APX3330 | RVECs | Reduced CI | [30] |
| APX3330 | ARPE-19 | Prevented apoptosis and reduced the upsurge of MCP-1 following induction of pathological stress with oxLDL | [28] |
| APX3330 | ARPE-19 | Reduced accumulation of intracellular ROS, secretion of VEGF and effectively blocked the upsurge of NF-κB in response to induced pathological stress by oxLDL | [28] |
| APX3330 | ARPE-19 | Protected the cells from a stress-induced senescence-like phenotype | [28] |
| APX3330 | ARPE-19 | Decreased the transcription activities of Nrf2/Nrf1, p53, NF-κB, HIF-1, CBF/NF-Y, YY1, MTF1 and HSF-1 | [28] |
| APX3330 | Rf/6a | Reduced p65 expression and NF-κB transcriptional activity | [55] |
| APX3330 | Rf/6a | Dose-dependently downregulated the production of MCP-1 | [55] |
| APX3330 | Rf/6a | Reduced STAT3 and NF-κB DNA binding activity | [55] |
| APX3330 | Rf/6a | Dose-dependently suppressed angiogenesis (proliferation, migration and tube formation) | [55] |
| APX3330 | Rf/6a | Did not induce apoptosis | [55] |
| APX3330 and Bevacizumab (antibody) | Rf/6a | Additive decline in migration, tube formation and proliferation | [55] |
| APX2009APX2014 | HRECs; Rf/6a | Dose-dependently decreased choroidal sprouting, proliferation, tube formation and endothelial cell migration | [44] |
| APX2009APX2014 | HRECs | Dose-dependently reduced translocation of the p65 subunit of NF-κB into the nucleus and decreased downstream mRNA targets of NF-κB including VCAM1, CCL20 and VEGFA | [44] |
| APX2009APX2014 | HRECs | Did not induce apoptosis in a TUNEL assay and blocked cells from entering the S phase | [44] |
| In vivo | |||
| APX3330 | Vldlr−/− mice | Single IVT injection of 20 μM decreased neovascularization | [30] |
| APX3330 | L-CNV mice | Single IVT injection for final intraocular concentration of 20 μM suppressed L-CNV lesion area | [28,55] |
| APX3330 | L-CNV mice | IP injection twice a day at 50 mg/kg for 5 days on and 2 days off for two weeks reduced L-CNV volume by 25% | [44] |
| APX2009 | L-CNV mice | IP injection (25 mg/kg twice daily for two weeks) decreased L-CNV volume without causing systemic toxicity | [44] |
| APX3330 | L-CNV mice | Gavage administration of either 25 mg/kg or 50 mg/kg gavage of APX3330 twice daily for 14 days resulted in decrease of lesion size by >50% | Figure 3 |