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20.06.2018 | Interstitial Lung Disease

Dasatinib Suppresses TGFβ-Mediated Epithelial–Mesenchymal Transition in Alveolar Epithelial Cells and Inhibits Pulmonary Fibrosis

verfasst von: Ryota Kanemaru, Fumiyuki Takahashi, Motoyasu Kato, Yoichiro Mitsuishi, Ken Tajima, Hiroaki Ihara, Moulid Hidayat, Aditya Wirawan, Yoshika Koinuma, Daisuke Hayakawa, Shigehiro Yagishita, Ryo Ko, Tadashi Sato, Norihiro Harada, Yuzo Kodama, Fariz Nurwidya, Shinichi Sasaki, Shin-ichiro Niwa, Kazuhisa Takahashi

Erschienen in: Lung | Ausgabe 5/2018

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Abstract

Purpose

Transforming growth factor β (TGFβ)-mediated epithelial–mesenchymal transition (EMT) of alveolar epithelial cells contributes to pulmonary fibrosis. Dasatinib (DAS), a potent and broad-spectrum tyrosine kinase inhibitor, has been widely studied as an anti-cancer agent. However, the therapeutic application of DAS for pulmonary fibrosis has not been clarified. Our purpose here is to investigate the effect of DAS on TGFβ1-induced EMT in human alveolar and bronchial epithelial cells in vitro and to evaluate the efficacy of DAS on lung fibrosis in vivo.

Methods

TGFβ1-stimulated human alveolar epithelial (A549) and bronchial epithelial (BEAS-2B) cells were treated with or without DAS in vitro. Murine pulmonary fibrosis model was generated by injection of bleomycin (BLM).

Results

A549 and BEAS-2B cells exposed to TGFβ1 underwent EMT, as indicated by downregulation of epithelial protein E-cadherin and induction of the mesenchymal proteins, fibronectin and type I and type IV collagen. These effects were dramatically suppressed by DAS treatment, which also prevented Smad2 and Smad3 phosphorylation. DAS inhibited TGFβ1-induced cell motility and migration. Furthermore, DAS administration significantly attenuated lung fibrosis in mice by histological analysis. Treatment with DAS also significantly reduced the levels of collagen and fibronectin and phosphorylation of Smad2 in the lung tissues of the murine model.

Conclusions

These findings suggest that DAS inhibited TGFβ-mediated EMT of alveolar and bronchial epithelial cells and attenuated BLM-induced lung fibrosis in mice by suppressing the TGFβ/Smad pathway. DAS may be a promising and novel anti-fibrotic agent for preventing lung fibrosis.

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Flaherty KR, Colby TV, Travis WD, Toews GB, Mumford J, Murray S et al (2003) Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease. Am J Respir Crit Care Med 167:1410–1415CrossRefPubMed

Kolosova I, Nethery D, Kern JA (2011) Role of Smad2/3 and p38 MAP kinase in TGF-beta1-induced epithelial-mesenchymal transition of pulmonary epithelial cells. J Cell Physiol 226:1248–1254CrossRefPubMedPubMedCentral

Kasai H, Allen JT, Mason RM, Kamimura T, Zhang Z (2005) TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res 6:56CrossRefPubMedPubMedCentral

Chapman HA (2011) Epithelial-mesenchymal interactions in pulmonary fibrosis. Annu Rev Physiol 73:413–435CrossRefPubMed

King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK et al (2014) A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 370:2083–2092CrossRefPubMed

Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U et al. (2014) Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 370:2071–2082CrossRefPubMed

Xi Y, Tan K, Brumwell AN, Chen SC, Kim YH, Kim TJ et al (2014) Inhibition of epithelial-to-mesenchymal transition and pulmonary fibrosis by methacycline. Am J Respir Cell Mol Biol 50:51–60PubMedPubMedCentral

Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL (2004) Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305:399–401CrossRefPubMed

Weisberg E, Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD (2007) Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer 7:345–356CrossRefPubMed

10.

Rabenau KE, Dolan M, Yohe S, Ustun C (2014) Effectiveness of dasatinib in accelerated-phase chronic myeloid leukemia with p190 BCR-ABL1 and a second Philadelphia chromosome. Cancer Genet 207:109–110CrossRefPubMed

11.

Finn RS, Bengala C, Ibrahim N, Roche H, Sparano J, Strauss LC et al (2011) Dasatinib as a single agent in triple-negative breast cancer: results of an open-label phase 2 study. Clin Cancer Res 17:6905–6913CrossRefPubMed

12.

Yilmaz O, Oztay F, Kayalar O (2015) Dasatinib attenuated bleomycin-induced pulmonary fibrosis in mice. Growth Factors 33:366–375CrossRefPubMed

13.

Abdalla M, Thompson L, Gurley E, Burke S, Ujjin J, Newsome R et al (2015) Dasatinib inhibits TGFbeta-induced myofibroblast differentiation through Src-SRF Pathway. Eur J Pharmacol 769:134–142CrossRefPubMedPubMedCentral

14.

Minakata K, Takahashi F, Nara T, Hashimoto M, Tajima K, Murakami A et al (2012) Hypoxia induces gefitinib resistance in non-small-cell lung cancer with both mutant and wild-type epidermal growth factor receptors. Cancer Sci 103:1946–1954CrossRefPubMed

15.

Oku H, Shimizu T, Kawabata T, Nagira M, Hikita I, Ueyama A et al (2008) Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J Pharmacol 590:400–408CrossRefPubMed

16.

Enomoto N, Suda T, Kato M, Kaida Y, Nakamura Y, Imokawa S et al (2006) Quantitative analysis of fibroblastic foci in usual interstitial pneumonia. Chest 130:22–29CrossRefPubMed

17.

Ashcroft T, Simpson JM, Timbrell V (1988) Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol 41:467–470CrossRefPubMedPubMedCentral

18.

Takahashi F, Takahashi K, Okazaki T, Maeda K, Ienaga H, Maeda M et al (2001) Role of osteopontin in the pathogenesis of bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 24:264–271CrossRefPubMed

19.

Kantarjian H, Jabbour E, Grimley J, Kirkpatrick P (2006) Dasatinib. Nat Rev Drug Discov 5:717–718CrossRefPubMed

20.

Montero JC, Seoane S, Ocana A, Pandiella A (2011) Inhibition of SRC family kinases and receptor tyrosine kinases by dasatinib: possible combinations in solid tumors. Clin Cancer Res 17:5546–5552CrossRefPubMed

21.

Hu M, Che P, Han X, Cai GQ, Liu G, Antony V et al (2014) Therapeutic targeting of SRC kinase in myofibroblast differentiation and pulmonary fibrosis. J Pharmacol Exp Ther 351:87–95CrossRefPubMedPubMedCentral

22.

Chaudhary NI, Roth GJ, Hilberg F, Muller-Quernheim J, Prasse A, Zissel G et al (2007) Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis. Eur Respir J 29:976–985CrossRefPubMed

23.

Abdollahi A, Li M, Ping G, Plathow C, Domhan S, Kiessling F et al (2005) Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis. J Exp Med 201:925–935CrossRefPubMedPubMedCentral

24.

Cruz FF, Horta LF, Maia Lde A, Lopes-Pacheco M, da Silva AB, Morales MM et al (2016) Dasatinib reduces lung inflammation and fibrosis in acute experimental silicosis. PLoS ONE 11:e0147005CrossRefPubMedPubMedCentral

25.

Harada T, Watanabe K, Nabeshima K, Hamasaki M, Iwasaki H (2013) Prognostic significance of fibroblastic foci in usual interstitial pneumonia and non-specific interstitial pneumonia. Respirology 18:278–283CrossRefPubMed

26.

Lomas NJ, Watts KL, Akram KM, Forsyth NR, Spiteri MA (2012) Idiopathic pulmonary fibrosis: immunohistochemical analysis provides fresh insights into lung tissue remodelling with implications for novel prognostic markers. Int J Clin Exp Pathol 5:58–71PubMedPubMedCentral

27.

Bartscht T, Rosien B, Rades D, Kaufmann R, Biersack H, Lehnert H et al (2015) Dasatinib blocks transcriptional and promigratory responses to transforming growth factor-beta in pancreatic adenocarcinoma cells through inhibition of Smad signalling: implications for in vivo mode of action. Mol Cancer 14:199CrossRefPubMedPubMedCentral

28.

Chung JH, Rho JK, Xu X, Lee JS, Yoon HI, Lee CT et al (2011) Clinical and molecular evidences of epithelial to mesenchymal transition in acquired resistance to EGFR-TKIs. Lung Cancer 73:176–182CrossRefPubMed

29.

Wilson C, Nicholes K, Bustos D, Lin E, Song Q, Stephan JP et al (2014) Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition. Oncotarget 5:7328–7341CrossRefPubMedPubMedCentral

30.

Sesumi Y, Suda K, Mizuuchi H, Kobayashi Y, Sato K, Chiba M et al (2017) Effect of dasatinib on EMT-mediated-mechanism of resistance against EGFR inhibitors in lung cancer cells. Lung Cancer 104:85–90CrossRefPubMed

31.

Mohammadalipour A, Karimi J, Khodadadi I, Solgi G, Hashemnia M, Sheikh N et al (2017) Dasatinib prevent hepatic fibrosis induced by carbon tetrachloride (CCl4) via anti-inflammatory and antioxidant mechanism. Immunopharmacol Immunotoxicol 39:19–27CrossRefPubMed

32.

Balasubramanian S, Pleasant DL, Kasiganesan H, Quinones L, Zhang Y, Sundararaj KP et al (2015) Dasatinib attenuates pressure overload induced cardiac fibrosis in a murine transverse aortic constriction model. PLoS ONE 10:e0140273CrossRefPubMedPubMedCentral

33.

Bergeron A, Rea D, Levy V, Picard C, Meignin V, Tamburini J et al (2007) Lung abnormalities after dasatinib treatment for chronic myeloid leukemia: a case series. Am J Respir Crit Care Med 176:814–818CrossRefPubMed

Titel: Dasatinib Suppresses TGFβ-Mediated Epithelial–Mesenchymal Transition in Alveolar Epithelial Cells and Inhibits Pulmonary Fibrosis
verfasst von: Ryota Kanemaru
Fumiyuki Takahashi
Motoyasu Kato
Yoichiro Mitsuishi
Ken Tajima
Hiroaki Ihara
Moulid Hidayat
Aditya Wirawan
Yoshika Koinuma
Daisuke Hayakawa
Shigehiro Yagishita
Ryo Ko
Tadashi Sato
Norihiro Harada
Yuzo Kodama
Fariz Nurwidya
Shinichi Sasaki
Shin-ichiro Niwa
Kazuhisa Takahashi
Publikationsdatum: 20.06.2018
Verlag: Springer US
Erschienen in: Lung / Ausgabe 5/2018
Print ISSN: 0341-2040
Elektronische ISSN: 1432-1750
DOI: https://doi.org/10.1007/s00408-018-0134-6

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Dasatinib Suppresses TGFβ-Mediated Epithelial–Mesenchymal Transition in Alveolar Epithelial Cells and Inhibits Pulmonary Fibrosis