Small Molecule Anti-Angiogenic Probes of the Ubiquitin Proteasome Pathway: Potential Application to Choroidal Neovascularization

Abstract

HCECs share with HUVECs a similar response to UPP inhibitors, suggesting that this well-conserved pathway that regulates angioinflammatory mechanisms could be exploited for drug-targeting in the development of novel agents for CNV treatment.

Withaferin A Targets Intermediate Filaments Glial Fibrillary Acidic Protein and Vimentin in a Model of Retinal Gliosis

“…Importantly, corneal angiogenesis was also simultaneously inhibited with 2 mg/kg of WFA in this chemical injury model, and without adverse effects on corneal resurfacing of denuded epithelium or on pre-existing limbal vasculature (10). Furthermore, we show that measurable levels of WFA (3 ng/l) in serum are achieved 6 h after a single 10 mg/kg intraperitoneal injection (supplemental data); the 2 mg/kg dose of WFA thus provides a systemic anti-inflammatory dose sufficient to down-regulate transcription factor NF-B activation (18,54,55). This posit is consistent with our previous finding that production of the potent inflammatory mediator TNF-␣ (56) is also blocked in vivo at this WFA dose (18).…”

Grape Seed Procyanidin B2 Inhibits Human Aortic Smooth Muscle Cell Proliferation and Migration Induced by Advanced Glycation End Products

“…41) Recent studies have reported that UCH-L1 exhibited anti-angiogenesis activity by affecting the development of choroidal new vessels in age-related macular degeneration disease. 42,43) Our previous experiments have shown that the expression of UCH-L1 in the retinopathy of diabetic rats was significantly lower than that of control rats by the proteomic technique. Treating with GSPE significantly increased the expression of UCH-L1 in diabetic rats.…”

Withanolides and Related Steroids

“…), thus the methyl ketal 255 is probably formed during isolation. Nicotra et al reported the isomeric clorohydrin, jaborosalactone 37 (256), from Jaborosa rotacea (120). Interestingly, the D 2 -withanolide 257 was present in Jaborosa caulescens var.…”

“…Withaferin A and withanolide D (508) also displayed antiangiogenic activity in human choroidal endothelial cells (HCECs). These results may lead to novel treatments of choroidal neovascularization, the major contributor to age-related macular degeneration and one of the leading causes of irreversible blindness in the Western hemisphere (256). Physalin B (463) has been identified recently as an inhibitor of the ubiquitin-mediated proteasome pathway in the DLD-1 human colon cancer cell line, producing an accumulation of ubiquitinated proteins and inhibiting TNFa-induced NF-kB activation (257).…”