Publication: In vitro and ex vivo anti-fibrotic effects of LY2109761, a small molecule inhibitor against TGF-β
Issued Date
2018-09-15
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ISSN
10960333
0041008X
0041008X
Other identifier(s)
2-s2.0-85049915333
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Mahidol University
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SCOPUS
Bibliographic Citation
Toxicology and Applied Pharmacology. Vol.355, (2018), 127-137
Suggested Citation
Theerut Luangmonkong, Su Suriguga, Adhyatmika Adhyatmika, Amirah Adlia, Dorenda Oosterhuis, Chuthamanee Suthisisang, Koert P. de Jong, Henricus A.M. Mutsaers, Peter Olinga In vitro and ex vivo anti-fibrotic effects of LY2109761, a small molecule inhibitor against TGF-β. Toxicology and Applied Pharmacology. Vol.355, (2018), 127-137. doi:10.1016/j.taap.2018.07.001 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/47297
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Title
In vitro and ex vivo anti-fibrotic effects of LY2109761, a small molecule inhibitor against TGF-β
Abstract
© 2018 Elsevier Inc. Fibrosis is a pathophysiological state characterized by the excessive formation/deposition of fibrous extracellular matrix. Transforming growth factor-beta (TGF-β) is a central profibrotic mediator, and targeting TGF-β is a promising strategy in the development of drugs for the treatment of fibrosis. Therefore, the effect of LY2109761, a small molecule inhibitor against TGF-β with targets beyond TGF-β signaling, on fibrogenesis was elucidated in vitro (HepG2 cells and LX-2 cells) and ex vivo (human and rat precision-cut liver slices). Our results displayed an anti-fibrotic effect of LY2109761, as it markedly down-regulated gene and protein expression of collagen type 1, as well as gene expression of the inhibitor of metalloproteinases 1. This effect on fibrosis markers was partially mediated by targeting TGF-β signaling, seeing that LY2109761 inhibited TGF-β1 gene expression and SMAD2 protein phosphorylation. Interestingly, particularly at a high concentration, LY2109761 decreased SMAD1 protein phosphorylation and gene expression of the inhibitor of DNA binding 1, which appeared to be TGF-β-independent effects. In conclusion, LY2109761 exhibited preclinical anti-fibrotic effects via both TGF-β-dependent and -independent pathways. These results illustrate that small molecule inhibitors directed against TGF-β could possibly influence numerous signaling pathways and thereby mitigate fibrogenesis.