Largazole Inhibits Ocular Angiogenesis by Modulating the Expression of VEGFR2 and p21

Abstract

Ocular angiogenic diseases, characterized by abnormal blood vessel formation in the eye, are the leading cause of blindness. Although Anti-VEGF therapy is the first-line treatment in the market, a substantial number of patients are refractory to it or may develop resistance over time. As uncontrolled proliferation of vascular endothelial cells is one of the characteristic features of pathological neovascularization, we aimed to investigate the role of the class I histone deacetylase (HDAC) inhibitor Largazole, a cyclodepsipeptide from a marine cyanobacterium, in ocular angiogenesis. Our study showed that Largazole strongly inhibits retinal vascular endothelial cell viability, proliferation, and the ability to form tube-like structures. Largazole strongly inhibits the vessel outgrowth from choroidal explants in choroid sprouting assay while it does not affect the quiescent choroidal vasculature. Largazole also inhibits vessel outgrowth from metatarsal bones in metatarsal sprouting assay without affecting pericytes coverage. We further demonstrated a cooperative effect between Largazole and an approved anti-VEGF drug, Alflibercept. Mechanistically, Largazole strongly inhibits the expression of VEGFR2 and leads to an increased expression of cell cycle inhibitor, p21. Taken together, our study provides compelling evidence on the anti-angiogenic role of Largazole that exerts its function through mediating different signaling pathways.

Marine Natural Products Rescuing the Eye: A Narrative Review

“…HDACs control gene expression by modifying the structure of chromatin, which is the complex of DNA and proteins found in the nucleus of cells. Through its inhibition, largazole downregulates the expression of pro-angiogenetic factors and upregulates anti-angiogenetic mediators [27,54]. Therefore, largazole has been explored in different eye disorders for its anti-inflammatory and anti-angiogenetic properties [27,54].…”

“…Through its inhibition, largazole downregulates the expression of pro-angiogenetic factors and upregulates anti-angiogenetic mediators [27,54]. Therefore, largazole has been explored in different eye disorders for its anti-inflammatory and anti-angiogenetic properties [27,54]. Zhou et al evaluated the effect of largazole on inflammatory corneal angiogenesis in a mouse model of alkali-induced corneal neovascularization.…”

“…Specifically, they reported largazole inhibition of retinal vascular endothelial cell viability and proliferation in vitro. Moreover, in ex vivo models, largazole reduced the vessel outgrowth from choroidal explants in a choroid sprouting assay and demonstrated a cooperative effect with aflibercept, an FDA-approved anti-VEGF drug currently used in clinical practice [54] (Table 2).…”

Depsipeptides Targeting Tumor Cells: Milestones from In Vitro to Clinical Trials

“…Largazole inhibited hypoxia-inducible factor and VEGF receptor 2, showed anti-angiogenic activities in vitro [ 125 ], and upregulated p21, a cell cycle inhibitor [ 126 ]. It also upregulated E-cadherin and increased its association with γ-catenin in breast cancer cells (MDA-MB-231), thus suppressing their invasiveness [ 127 ].…”

“…Apratoxin can downregulate receptor tyrosine kinases and VEGF-A in colorectal tumor models [ 188 ]. Specifically, apratoxin S4 demonstrated potent anti-angiogenic activity as it prevented pathological ocular neovascularization in vivo [ 126 ].…”