State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China.
Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300457, China.
Int J Mol Sci. 2021 Feb 17;22(4):1985. doi: 10.3390/ijms22041985.
Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.
特发性肺纤维化（IPF）是一种致命的、与年龄相关的肺部疾病。尼达尼布是一种受体酪氨酸激酶抑制剂，也是仅有的两种治疗特发性肺纤维化的药物之一。瑞戈非尼是一种新型的、口服活性的、多激酶抑制剂，与尼达尼布具有相似的靶点，用于治疗结直肠癌和胃肠道间质瘤患者。在这项研究中，我们首先确定瑞戈非尼可以减轻博来霉素诱导的小鼠肺纤维化。体内实验表明，瑞戈非尼抑制胶原积累和肌成纤维细胞激活。进一步的体外机制研究表明，瑞戈非尼通过抑制转化生长因子（TGF）-β1/ Smad 和非 Smad 信号通路，抑制肌成纤维细胞的激活和迁移以及细胞外基质的产生。体外研究还表明，瑞戈非尼通过抑制 TGF-β1/mTOR（雷帕霉素的机制靶点）信号通路，抑制肌成纤维细胞中的自噬，并促进肌成纤维细胞中的凋亡，从而增强肌成纤维细胞中的自噬。总之，瑞戈非尼通过抑制 TGF-β1 信号通路来减轻博来霉素诱导的肺纤维化。
Zotero 插件
