Cargando…
AZD6738 Inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/P53 and PI3K/AKT pathways
Trabeculectomy can effectively reduce intraocular pressure (IOP) in glaucoma patients, the long-term surgical failure is due to the excessive proliferation and fibrotic response of conjunctival fibroblasts which causes the subconjunctival scar and non-functional filtering bleb. In this study, we dem...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9530343/ https://www.ncbi.nlm.nih.gov/pubmed/36204234 http://dx.doi.org/10.3389/fphar.2022.990401 |
_version_ | 1784801661308370944 |
---|---|
author | Huang, Longxiang Ye, Qin Lan, Chunlin Wang, Xiaohui Zhu, Yihua |
author_facet | Huang, Longxiang Ye, Qin Lan, Chunlin Wang, Xiaohui Zhu, Yihua |
author_sort | Huang, Longxiang |
collection | PubMed |
description | Trabeculectomy can effectively reduce intraocular pressure (IOP) in glaucoma patients, the long-term surgical failure is due to the excessive proliferation and fibrotic response of conjunctival fibroblasts which causes the subconjunctival scar and non-functional filtering bleb. In this study, we demonstrated that AZD6738 (Ceralasertib), a novel potent ataxia telangiectasia and Rad3-related (ATR) kinase inhibitor, can inhibit the fibrotic response of conjunctival fibroblasts for the first time. Our in vitro study demonstrated that AZD6738 inhibited the level and the phosphorylation of checkpoint kinase 1 (CHK1), reduced TGF-β1-induced cell proliferation and migration, and induced apoptosis of human conjunctival fibroblasts (HConFs) in the high-dose group (5 μM). Low-dose AZD6738 (0.1 μM) inhibited the phosphorylation of CHK1 and reduce fibrotic response but did not promote apoptosis of HConFs. Further molecular research indicated that AZD6738 regulates survival and apoptosis of HConFs by balancing the CHK1/P53 and PI3K/AKT pathways, and inhibiting TGF-β1-induced fibrotic response including myofibroblast activation and relative extracellular matrix (ECM) protein synthesis such as fibronectin (FN), collagen Ⅰ (COL1) and collagen Ⅳ (COL4) through a dual pharmacological mechanism. Hence, our results show that AZD6738 inhibits fibrotic responses in cultured HConFs in vitro and may become a potential therapeutic option for anti-subconjunctival scarring after trabeculectomy. |
format | Online Article Text |
id | pubmed-9530343 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95303432022-10-05 AZD6738 Inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/P53 and PI3K/AKT pathways Huang, Longxiang Ye, Qin Lan, Chunlin Wang, Xiaohui Zhu, Yihua Front Pharmacol Pharmacology Trabeculectomy can effectively reduce intraocular pressure (IOP) in glaucoma patients, the long-term surgical failure is due to the excessive proliferation and fibrotic response of conjunctival fibroblasts which causes the subconjunctival scar and non-functional filtering bleb. In this study, we demonstrated that AZD6738 (Ceralasertib), a novel potent ataxia telangiectasia and Rad3-related (ATR) kinase inhibitor, can inhibit the fibrotic response of conjunctival fibroblasts for the first time. Our in vitro study demonstrated that AZD6738 inhibited the level and the phosphorylation of checkpoint kinase 1 (CHK1), reduced TGF-β1-induced cell proliferation and migration, and induced apoptosis of human conjunctival fibroblasts (HConFs) in the high-dose group (5 μM). Low-dose AZD6738 (0.1 μM) inhibited the phosphorylation of CHK1 and reduce fibrotic response but did not promote apoptosis of HConFs. Further molecular research indicated that AZD6738 regulates survival and apoptosis of HConFs by balancing the CHK1/P53 and PI3K/AKT pathways, and inhibiting TGF-β1-induced fibrotic response including myofibroblast activation and relative extracellular matrix (ECM) protein synthesis such as fibronectin (FN), collagen Ⅰ (COL1) and collagen Ⅳ (COL4) through a dual pharmacological mechanism. Hence, our results show that AZD6738 inhibits fibrotic responses in cultured HConFs in vitro and may become a potential therapeutic option for anti-subconjunctival scarring after trabeculectomy. Frontiers Media S.A. 2022-09-20 /pmc/articles/PMC9530343/ /pubmed/36204234 http://dx.doi.org/10.3389/fphar.2022.990401 Text en Copyright © 2022 Huang, Ye, Lan, Wang and Zhu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Huang, Longxiang Ye, Qin Lan, Chunlin Wang, Xiaohui Zhu, Yihua AZD6738 Inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/P53 and PI3K/AKT pathways |
title | AZD6738 Inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/P53 and PI3K/AKT pathways |
title_full | AZD6738 Inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/P53 and PI3K/AKT pathways |
title_fullStr | AZD6738 Inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/P53 and PI3K/AKT pathways |
title_full_unstemmed | AZD6738 Inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/P53 and PI3K/AKT pathways |
title_short | AZD6738 Inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/P53 and PI3K/AKT pathways |
title_sort | azd6738 inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/p53 and pi3k/akt pathways |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9530343/ https://www.ncbi.nlm.nih.gov/pubmed/36204234 http://dx.doi.org/10.3389/fphar.2022.990401 |
work_keys_str_mv | AT huanglongxiang azd6738inhibitsfibroticresponseofconjunctivalfibroblastsbyregulatingcheckpointkinase1p53andpi3kaktpathways AT yeqin azd6738inhibitsfibroticresponseofconjunctivalfibroblastsbyregulatingcheckpointkinase1p53andpi3kaktpathways AT lanchunlin azd6738inhibitsfibroticresponseofconjunctivalfibroblastsbyregulatingcheckpointkinase1p53andpi3kaktpathways AT wangxiaohui azd6738inhibitsfibroticresponseofconjunctivalfibroblastsbyregulatingcheckpointkinase1p53andpi3kaktpathways AT zhuyihua azd6738inhibitsfibroticresponseofconjunctivalfibroblastsbyregulatingcheckpointkinase1p53andpi3kaktpathways |