The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China.
Fujian Obstetrics and Gynecology Hospital, Fuzhou, Fujian, China.
Biochem Pharmacol. 2022 Dec;206:115340. doi: 10.1016/j.bcp.2022.115340. Epub 2022 Nov 5.
In this study, we report that AZD6738 (Ceralasertib), a novel potent ataxia telangiectasia and Rad3-related (ATR) kinase inhibitor, can decrease intraocular pressure (IOP) and inhibits fibrotic response in the trabecular meshwork (TM). We established mice TGF-β2-induced high IOP model and revealed that AZD6738 could effectively decrease IOP in the mice model and reduce TGF-β2-induced hyperplasia, collagen production, fibrosis, and extracellular matrix (ECM) remodeling in the TM by downregulating checkpoint kinase 1 (CHK1) level. Further, we demonstrated that AZD6738 reduces cell viability and migration, and inhibit the expression of fibrosis-related factors including fibronectin (FN), α-smooth muscle actin (α-SMA), laminin subunit beta 1 (LAMB1), matrix metallopeptidase (MMP) family including MMP2 and MMP9, collagen Ⅰ (COL1), and collagen Ⅳ (COL4), reduce gap junctions, altered cytoskeleton and nitric oxide production in TGF-β1-induced human trabecular meshwork cells (HTMCs) through the CHK1/P53 pathway, which were affected aqueous humor (AH) production and outflow pathway. In addition, we preliminarily verified the safety of the AZD6738 in topical ophthalmic use. Hence, our results demonstrate that AZD6738 may become a potential therapeutic option for anti-glaucoma.
在这项研究中，我们报告称，AZD6738（Ceralasertib）是一种新型有效的共济失调毛细血管扩张症和 Rad3 相关（ATR）激酶抑制剂，可降低眼内压（IOP）并抑制小梁网（TM）中的纤维化反应。我们建立了 TGF-β2 诱导的小鼠高 IOP 模型，揭示了 AZD6738 可有效降低小鼠模型中的 IOP，并通过下调检查点激酶 1（CHK1）水平，减少 TGF-β2 诱导的 TM 增生、胶原产生、纤维化和细胞外基质（ECM）重塑。此外，我们证明 AZD6738 可降低细胞活力和迁移，并抑制纤维化相关因子的表达，包括纤维连接蛋白（FN）、α-平滑肌肌动蛋白（α-SMA）、层粘连蛋白亚基β1（LAMB1）、基质金属蛋白酶（MMP）家族包括 MMP2 和 MMP9、胶原 Ⅰ（COL1）和胶原 Ⅳ（COL4），减少 TGF-β1 诱导的人小梁网细胞（HTMCs）中的缝隙连接，改变细胞骨架和一氧化氮产生，通过 CHK1/P53 通路影响房水（AH）产生和流出途径。此外，我们初步验证了 AZD6738 局部眼用的安全性。因此，我们的结果表明，AZD6738 可能成为一种潜在的抗青光眼治疗选择。
