Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway.
Animals
Apoptosis
/ drug effects
Autophagy
/ drug effects
Bleomycin
Cell Movement
/ drug effects
Down-Regulation
/ drug effects
Extracellular Matrix
/ drug effects
Fibroblasts
/ drug effects
Idiopathic Pulmonary Fibrosis
/ drug therapy
Male
Mice
Mice, Inbred C57BL
NIH 3T3 Cells
Phenylurea Compounds
/ pharmacology
Pyridines
/ pharmacology
Signal Transduction
Smad Proteins
/ metabolism
TOR Serine-Threonine Kinases
/ metabolism
Transforming Growth Factor beta1
/ metabolism
TGF-β1 signaling pathway
myofibroblasts
pulmonary fibrosis
regorafenib
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
17 Feb 2021
17 Feb 2021
Historique:
received:
15
01
2021
revised:
01
02
2021
accepted:
11
02
2021
entrez:
6
3
2021
pubmed:
7
3
2021
medline:
14
4
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33671452
pii: ijms22041985
doi: 10.3390/ijms22041985
pmc: PMC7922359
pii:
doi:
Substances chimiques
Phenylurea Compounds
0
Pyridines
0
Smad Proteins
0
Transforming Growth Factor beta1
0
Bleomycin
11056-06-7
regorafenib
24T2A1DOYB
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : National Natural Science Foundation of China
ID : Grant 82072660, 82070060, 82000073
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