Radotinib attenuates TGFß -mediated pulmonary fibrosis in vitro and in vivo: exploring the potential of drug repurposing.
BMC Pharmacol Toxicol
; 23(1): 93, 2022 12 15.
Article
in En
| MEDLINE
| ID: mdl-36522756
ABSTRACT
BACKGROUND:
Tyrosine kinase (TK) plays a crucial role in the pathogenesis of idiopathic pulmonary fibrosis. Here, we aimed to investigate whether radotinib (Rb) could inhibit pulmonary fibrosis by inhibiting TK in vitro and in vivo.METHODS:
The antifibrotic effects of Rb in transforming growth factor-ß (TGF-ß)1-stimulated A549 cells were determined using real-time polymerase chain reaction, western blotting, and immunocytochemistry assays. Rb inhibition of bleomycin-induced lung fibrosis in Sprague Dawley (SD) rats was determined by histopathological andâ immunohistochemical analyses. Rb-interfering metabolites were analyzed using LC-MS/MS.RESULTS:
Rb concentrations of up to 1000 nM did not affect the viability of A549 cells, but Rb (30 nM) significantly reduced expression of TGF-ß1 (10 ng/mL)-induced ECM factors, such as Snail, Twist, and F-actin. Rb also regulated TGF-ß1-overexpressed signal cascades, such as fibronectin and α-smooth muscle actin. Furthermore, Rb attenuated the phosphorylation of Smad2 and phosphorylation of kinases, such as, extracellular signal-regulated kinase, and protein kinase B. In the inhibitory test against bleomycin (5 mg/kg)-induced lung fibrosis, the Rb (30 mg/kg/daily)-treated group showed a half-pulmonary fibrosis region compared to the positive control group. In addition, Rb significantly reduced collagen type I and fibronectin expression in the bleomycin-induced fibrotic region of SD rats. Further, the identified metabolite pantothenic acid was not altered by Rb.CONCLUSION:
Taken together, these results indicate that Rb inhibits TGF-ß1-induced pulmonary fibrosis both in vitro and in vivo. These findings suggest that Rb may be an effective treatment for pulmonary fibrosis-related disorders and idiopathic pulmonary fibrosis.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Transforming Growth Factor beta
/
Idiopathic Pulmonary Fibrosis
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
BMC Pharmacol Toxicol
Year:
2022
Document type:
Article