title: 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.
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.
authors.affiliation: 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.
authors.forename: Shu-fang
authors.initials: SF
authors.lastname: Jin
authors.affiliation: 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.
authors.forename: Hai-long
authors.initials: HL
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Zhong-long
authors.initials: ZL
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Shui-ting
authors.initials: ST
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Chen-ping
authors.initials: CP
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Yue
authors.initials: Y
authors.lastname: He
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis / Q000188:drug therapy*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D051899:Smad2 Protein / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism*; D013329:Structure-Activity Relationship; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C497782:SMAD2 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051901:Smad4 Protein; D053773:Transforming Growth Factor beta1; C574818:XL413 compound; C093844:pirfenidone; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Cell division cycle 7; Differentiation; Pirfenidone; Proliferation; Smads