Abstract
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.
Highlights
Reversible small-molecule epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), including gefitinib (Iressa) and erlotinib (Tarceva), display dramatic therapeutic efficacy in NSCLC patients that have EGFR-activating mutations, and are recommended as the standard first-line therapy in NSCLC [1, 2]
We used transforming growth factor (TGF)-β to stimulate pulmonary fibrosis in lung fibroblast HFL-1 cells, since TGF-β is a well-established inducer of fibrosis
TGF-β treatment induced fibrosis in HFL-1 cells, and addition of metformin effectively decreased the expression of those fibrotic markers
Summary
Reversible small-molecule epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), including gefitinib (Iressa) and erlotinib (Tarceva), display dramatic therapeutic efficacy in NSCLC patients that have EGFR-activating mutations, and are recommended as the standard first-line therapy in NSCLC [1, 2]. Despite excellent initial clinical responses, these drugs might promote interstitial lung disease (ILD), which is a less common but lethal side-effect that restricts the therapeutic efficacy of these agents [3]. The incidence of EGFR-TKI-associated ILD has been described for both gefitinib (2.4%) and erlotinib (1%) [4]. The incidence of EGFR-TKI-associated ILD appears comparatively higher in Asians than in Caucasians, as demonstrated in two large, multiinstitutional studies reporting its incidence in Japan at 3.5–4.0% [5, 6], as compared with that of 0.3% in the U.S [7]. No specific treatment is available for EGFR-TKIassociated ILD, and supportive therapy largely includes oxygen, corticosteroids, or assisted ventilation, with an www.impactjournals.com/oncotarget approximate 30%–40% mortality of the disease. Acute and innovative treatment strategies are urgently needed to overcome the lethal side-effect of EGFR-TKIs
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