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Exp Cell Res. 2015 Dec 10;339(2):289-99. doi: 10.1016/j.yexcr.2015.11.013. Epub 2015 Nov 14.

XL413, a cell division cycle 7 kinase inhibitor enhanced the anti-fibrotic effect of pirfenidone on TGF-β1-stimulated C3H10T1/2 cells via Smad2/4.

Author information

1
Department of Oral Maxillofacial-Head and Neck Oncology, Faculty of Oral and Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China.
2
Department of Oral Maxillofacial-Head and Neck Oncology, Faculty of Oral and Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China. Electronic address: yuehe@sjtu.edu.cn.

Abstract

Pirfenidone is an orally bioavailable synthetic compound with therapeutic potential for idiopathic pulmonary fibrosis. It is thought to act through antioxidant and anti-fibrotic pathways. Pirfenidone inhibits proliferation and/or myofibroblast differentiation of a wide range of cell types, however, little studies have analyzed the effect of pirfenidone on the mesenchymal stem cells, which play an important role on the origin of myofibroblasts. We recently found that pirfenidone had anti-proliferative activity via G1 phase arrest and cell division cycle 7 (Cdc7) kinase expression decrease in transforming growth factor-β1 (TGF-β1)-stimulated murine mesenchymal stem C3H10T1/2 cells. Pirfenidone also had inhibiting effect on the migration and α-SMA expression. Moreover, in this study we showed for the first time that Cdc7 inhibitor XL413 enhanced the anti-fibrotic activity of pirfenidone via depressed the expression of Smad2/4 proteins, and also prevented the nuclear accumulation and translocation of Smad2 protein. In conclusion, we demonstrated that pirfenidone inhibited proliferation, migration and differentiation of TGF-β1-stimulated C3H10T1/2 cells, which could be enhanced by Cdc7 inhibitor XL413, via Smad2/4. Combination with pirfenidone and XL413 might provide a potential candidate for the treatment of TGF-β1 associated fibrosis. It needs in vivo studies to further validate its therapeutic function and safety in the future.

KEYWORDS:

Cell division cycle 7; Differentiation; Pirfenidone; Proliferation; Smads

PMID:
26589264
DOI:
10.1016/j.yexcr.2015.11.013
[Indexed for MEDLINE]

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