TY - JOUR
T1 - The Multi-Modal Effect of the Anti-fibrotic Drug Pirfenidone on NSCLC
AU - Marwitz, Sebastian
AU - Turkowski, Kati
AU - Nitschkowski, Dörte
AU - Weigert, Andreas
AU - Brandenburg, Julius
AU - Reiling, Norbert
AU - Thomas, Michael
AU - Reck, Martin
AU - Drömann, Daniel
AU - Seeger, Werner
AU - Rabe, Klaus F.
AU - Savai, Rajkumar
AU - Goldmann, Torsten
N1 - Funding Information:
This work was supported by the Max Planck Society (RS), Verein zur Förderung der Krebsforschung in Gießen e.V (RS), Von-Behring-Röntgen-Stiftung, a Rhön Klinikum AG grant, LOEWE Center Frankfurt Cancer Institute (FCI) funded by the Hessen State Ministry for Higher Education, Research and the Arts [III L 5 - 519/03/03.001 - (0015)], Cardio-Pulmonary Institute (CPI), and the German Center for Lung Research (DZL) (RS, TG).
Publisher Copyright:
© Copyright © 2020 Marwitz, Turkowski, Nitschkowski, Weigert, Brandenburg, Reiling, Thomas, Reck, Drömann, Seeger, Rabe, Savai and Goldmann.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/1/21
Y1 - 2020/1/21
N2 - Although immune checkpoint and targeted therapies offer remarkable benefits for lung cancer treatment, some patients do not qualify for these regimens or do not exhibit consistent benefit. Provided that lung cancer appears to be driven by transforming growth factor beta signaling, we investigated the single drug potency of Pirfenidone, an approved drug for the treatment of lung fibrosis. Five human lung cancer cell lines and one murine line were investigated for transforming growth factor beta inhibition via Pirfenidone by using flow cytometry, In-Cell western analysis, proliferation assays as well as comprehensive analyses of the transcriptome with subsequent bioinformatics analysis. Overall, Pirfenidone induced cell cycle arrest, down-regulated SMAD expression and reduced proliferation in lung cancer. Furthermore, cell stress pathways and pro-apoptotic signaling may be mediated by reduced expression of Survivin. A murine subcutaneous model was used to assess the in vivo drug efficacy of Pirfenidone and showed reduced tumor growth and increased infiltration of T cells and NK cells. This data warrant further clinical evaluation of Pirfenidone with advanced non-small cell lung cancer. The observed in vitro and in vivo effects point to a substantial benefit for using Pirfenidone to reactivate the local immune response and possible application in conjunction with current immunotherapies.
AB - Although immune checkpoint and targeted therapies offer remarkable benefits for lung cancer treatment, some patients do not qualify for these regimens or do not exhibit consistent benefit. Provided that lung cancer appears to be driven by transforming growth factor beta signaling, we investigated the single drug potency of Pirfenidone, an approved drug for the treatment of lung fibrosis. Five human lung cancer cell lines and one murine line were investigated for transforming growth factor beta inhibition via Pirfenidone by using flow cytometry, In-Cell western analysis, proliferation assays as well as comprehensive analyses of the transcriptome with subsequent bioinformatics analysis. Overall, Pirfenidone induced cell cycle arrest, down-regulated SMAD expression and reduced proliferation in lung cancer. Furthermore, cell stress pathways and pro-apoptotic signaling may be mediated by reduced expression of Survivin. A murine subcutaneous model was used to assess the in vivo drug efficacy of Pirfenidone and showed reduced tumor growth and increased infiltration of T cells and NK cells. This data warrant further clinical evaluation of Pirfenidone with advanced non-small cell lung cancer. The observed in vitro and in vivo effects point to a substantial benefit for using Pirfenidone to reactivate the local immune response and possible application in conjunction with current immunotherapies.
UR - http://www.scopus.com/inward/record.url?scp=85079070634&partnerID=8YFLogxK
U2 - 10.3389/fonc.2019.01550
DO - 10.3389/fonc.2019.01550
M3 - Journal articles
AN - SCOPUS:85079070634
SN - 2234-943X
VL - 9
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 1550
ER -