Effect of pirfenidone on rat hepatic stellate cell proliferation and collagen production

Sario, A. Di; Bendia, E.; Svegliati‐Baroni, Gianluca; Ridolfi, F.; Casini, Alessandro; Ceni, E.; Saccomanno, S.; Marzioni, Marco; Trozzi, L.; Sterpetti, Paola; Taffetani, Silvia; Benedetti, Antonio

doi:10.1016/s0168-8278(02)00245-3

Cited by 115 publications

(79 citation statements)

References 40 publications

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“…In animal models of lung fibrosis, pirfenidone inhibited fibrosis and downregulated TGF-b, PDGF, and collagen synthesis (16)(17)(18). In liver fibrosis models, pirfenidone suppressed the proliferation of hepatic stellate cells, TGF-b mRNA expression, and the production of collagen type I (19,20). These reports suggest that pirfenidone exerts antifibrotic effects by inhibiting fibroblasts and the production of TGF-b, PDGF, and collagen type I.…”

Section: Introductionmentioning

confidence: 74%

Pirfenidone Inhibits Pancreatic Cancer Desmoplasia by Regulating Stellate Cells

et al. 2013

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Pancreatic stellate cells (PSC), which are implicated in desmoplasia in pancreatic cancer, enhance the malignancy of cancer cells and confer resistance to established treatments. We investigated whether the antifibrotic agent pirfenidone can suppress desmoplasia and exert antitumor effects against pancreatic cancer. Primary PSCs were established from pancreatic cancer tissue obtained during surgery. In vitro, pirfenidone inhibited the proliferation, invasiveness, and migration of PSCs in a dose-dependent manner. Although supernatants of untreated PSCs increased the proliferation, invasiveness, and migration of pancreatic cancer cells (PCC), supernatants of pirfenidone-treated PSCs decreased these effects. Exposure to PCC supernatant increased the production of platelet-derived growth factor-A, hepatic growth factor, collagen type I, fibronectin, and periostin in PSCs, which was significantly reduced by pirfenidone. Mice were subcutaneously implanted with PCCs (SUIT-2 cells) and PSCs into the right flank and PCCs alone into the left flank. Oral administration of pirfenidone to these mice significantly reduced tumor growth of co-implanted PCCs and PSCs, but not of PCCs alone. Pirfenidone also decreased the proliferation of PSCs and the deposition of collagen type I and periostin in tumors. In mice with orthotopic tumors consisting of PCCs co-implanted with PSCs, pirfenidone suppressed tumor growth, reduced the number of peritoneal disseminated nodules, and reduced the incidence of liver metastasis. Pirfenidone in combination with gemcitabine more effectively suppressed orthotopic tumor growth compared with pirfenidone or gemcitabine alone. In conclusion, our findings indicate that pirfenidone is a promising antitumor agent for pancreatic cancer, owing to its suppression of desmoplasia through regulating PSCs. Cancer Res; 73(7); 2345-56. Ó2013 AACR.

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Section: Introductionmentioning

confidence: 74%

Pirfenidone Inhibits Pancreatic Cancer Desmoplasia by Regulating Stellate Cells

et al. 2013

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“…Furthermore, pirfenidone has been revealed to suppress lung fibrosis through the downregulation of TGF-β, platelet-derived growth factor (PDGF) and collagen synthesis in a hamster model (10)(11)(12). In addition, it was shown to suppress liver fibrosis through the downregulation of TGF-β (13,14). Nintedanib has been demonstrated to suppress the deterioration of FVC and the incidence of acute exacerbation in patients with IPF (15,16).…”

Section: Introductionmentioning

confidence: 99%

Pirfenidone may revert the epithelial-to-mesenchymal transition in human lung adenocarcinoma

et al. 2017

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Abstract. The epithelial-to-mesenchymal transition (EMT) in cancer is associated with invasion, metastasis and chemoresistance. Recent studies have revealed the increased expression of programmed death-ligand 1 (PD-L1) in cells undergoing EMT. The underlying mechanism of EMT involves transforming growth factor-β (TGF-β) and fibroblast growth factor-2 (FGF-2). Pirfenidone and the known EMT-suppressor nintedanib suppress pulmonary fibrosis partially through suppression of TGF-β. The present study aimed to determine whether pirfenidone has the potential to induce EMT-reversion, using nintedanib as a reference. The human lung adenocarcinoma cell lines A-549, HCC-827, and PC-9 were treated with TGF-β and FGF-2 to induce EMT. The EMT-induced cells were further treated with pirfenidone or nintedanib. Phenotypic alterations associated with EMT were assessed by examining the following: i) The expression levels of E-cadherin, vimentin, fibronectin and slug, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and fluorescent immunohistochemistry; ii) cell motility via wound-healing assays; and iii) the expression of PD-L1 using RT-qPCR. The combination of TGF-β and FGF-2 successfully induced EMT in all three cell lines, characterized by a significant reduction in E-cadherin expression in the A-549 and HCC-827 cells, increased expression levels of vimentin, fibronectin, slug and PD-L1, and increased cell motility in all three cell lines. Pirfenidone and nintedanib reverted all of these phenotypes, with the exception of unaltered E-cadherin expression in all three cell lines, and inconsistent expression of vimentin in the HCC-827 and PC-9 cells. Thus, pirfenidone and nintedanib have the ability to induce EMT-reversion in human lung adenocarcinoma.

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“…Many studies have reported that pyridone agents, such as pirfenidone (PFD), can attenuate fibrosis in many organs including pulmonary (21), cardiac (44), renal (39), and hepatic (10,11,32). As a newly developed water-soluble pyridone agent with potential broadspectrum antifibrotic characteristics, fluorofenidone [1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone; AKF-PD] can attenuate renal and cardiac fibrosis (8,34,45,48).…”

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confidence: 99%