Metformin attenuates gefitinib-induced exacerbation of pulmonary fibrosis by inhibition of TGF-β signaling pathway.
Interstitial lung disease (ILD) is a serious side-effect of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment. Therefore, it is necessary to study underlying mechanisms for the development of pulmonary fibrosis induced by EGFR-TKI and potential approaches to attenuate it. Metformin is a well-established and widely prescribed oral hypoglycemic drug, and has gained attention for its potential anticancer effects. Recent reports have also demonstrated its role in inhibiting epithelial-mesenchymal transition and fibrosis. However, it is unknown whether metformin attenuates EGFR-TKI-induced pulmonary fibrosis. The effect of metformin on EGFR-TKI-induced exacerbation of pulmonary fibrosis was examined in vitro and in vivo using MTT, Ki67 incorporation assay, flow cytometry, immunostaining, Western blot analysis, and a bleomycin-induced pulmonary fibrosis rat model. We found that in lung HFL-1 fibroblast cells, TGF-β or conditioned medium from TKI-treated lung cancer PC-9 cells or conditioned medium from TKI-resistant PC-9GR cells, induced significant fibrosis, as shown by increased expression of Collegen1a1 and α-actin, while metformin inhibited expression of fibrosis markers. Moreover, metformin decreased activation of TGF-β signaling as shown by decreased expression of pSMAD2 and pSMAD3. In vivo, oral administration of gefitinib exacerbated bleomycin-induced pulmonary fibrosis in rats, as demonstrated by HE staining and Masson staining. Significantly, oral co-administration of metformin suppressed exacerbation of bleomycin-induced pulmonary fibrosis by gefitinib. We have shown that metformin attenuates gefitinib-induced exacerbation of TGF-β or bleomycin-induced pulmonary fibrosis. These observations indicate metformin may be combined with EGFR-TKI to treat NSCLC patients.
Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing, China.
Li
L
Li
Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing, China.
Wenting
W
Huang
Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing, China.
Kunlin
K
Li
Department of Clinical Labratory, Daping Hospital, Third Military Medical University, Chongqing, China.
Kejun
K
Zhang
Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing, China.
Caiyu
C
Lin
Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing, China.
Rui
R
Han
Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing, China.
Conghua
C
Lu
Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing, China.
Yubo
Y
Wang
Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing, China.
Hengyi
H
Chen
Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing, China.
Fenfen
F
Sun
Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing, China.
Yong
Y
He
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D015153:Blotting, Western; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005434:Flow Cytometry; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry; D017563:Lung Diseases, Interstitial / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D011799:Quinazolines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D011799:Quinazolines; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D008687:Metformin; D000077156:Gefitinib
EGFR-TKI; TGF-β; metformin; pulmonary fibrosis