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Metformin attenuates gefitinib-induced exacerbation of pulmonary fibrosis by
inhibition of TGF-? signaling pathway
#MMPMID26497205
Li L
; Huang W
; Li K
; Zhang K
; Lin C
; Han R
; Lu C
; Wang Y
; Chen H
; Sun F
; He Y
Oncotarget
2015[Dec]; 6
(41
): 43605-19
PMID26497205
show ga
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-? 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 ?-actin, while
metformin inhibited expression of fibrosis markers. Moreover, metformin decreased
activation of TGF-? 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-? or bleomycin-induced pulmonary
fibrosis. These observations indicate metformin may be combined with EGFR-TKI to
treat NSCLC patients.
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