Exploring the Efficacy of AZD6738 in Corneal Neovascularization: Autophagy Enhancement and Angiogenesis Inhibition.

Purpose: This study aimed to investigate the therapeutic potential of AZD6738, an ataxia-telangiectasia and rad3-related (ATR) kinase inhibitor, in preventing corneal neovascularization (CNV) by exploring its effects on autophagy regulation and angiogenesis.

Methods

Human umbilical vein endothelial cells were cultured and treated with varying concentrations of AZD6738 and vascular endothelial growth factor (VEGF) to assess cell viability, migration, and tube formation. A corneal alkali burn model in Sprague-Dawley rats was established to evaluate the in vivo effects of AZD6738 on CNV. Autophagy was assessed using monodansylcadaverine (MDC) staining, western blotting, and qRT-PCR to measure the expression of autophagy-related markers and key proteins involved in the PI3K-AKT pathway. Immunohistochemistry and immunofluorescence staining were employed to examine histological changes and the expression of markers related to neovascularization and fibrosis.

Results

The study demonstrated that AZD6738 significantly inhibited cell viability in a dose-dependent manner. AZD6738 effectively reduced VEGF-induced cell migration and tube formation. Moreover, the introduction of AZD6738 enhanced autophagy, as indicated by increased MDC staining, upregulated Beclin1 expression, and an elevated LC3 II/I ratio. The inhibitor also suppressed the PI3K-AKT pathway, reducing VEGF and VEGFR2 expression, and decreasing the phosphorylation levels of AMPK and AKT. In an experimental CNV model, AZD6738 treatment resulted in a significant reduction in CNV, with fewer and shorter blood vessels observed, as well as changes in autophagy-related proteins.

Conclusions

AZD6738 showed potential in preventing CNV. Its ability to enhance autophagy and inhibit PI3K-AKT-VEGF pathways in angiogenesis suggests that AZD6738 could be an effective treatment strategy for CNV.