Metformin attenuates gefitinib-induced exacerbation of pulmonary fibrosis by inhibition of TGF-β signaling pathway.
Metformin attenuates gefitinib-induced exacerbation of pulmonary fibrosis by inhibition of TGF-β signaling pathway.
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二甲双胍通过抑制 TGF-β 信号通路减轻吉非替尼诱导的肺纤维化恶化
DOI：
10.18632/oncotarget.6186
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发表时间：
2015-12-22
期刊：
影响因子：
--
通讯作者：
He Y
中科院分区：
文献类型：
--
作者：
Li L;Huang W;Li K;Zhang K;Lin C;Han R;Lu C;Wang Y;Chen H;Sun F;He Y
间质性肺病（ILD）是表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂（TKI）治疗的一种严重副作用。因此，有必要研究EGFR-TKI诱导肺纤维化的潜在机制和潜在的方法来减轻它。二甲双胍是一种成熟的和广泛使用的口服降糖药物，并已获得关注，其潜在的抗癌作用。最近的报道也证明了其在抑制上皮-间质转化和纤维化中的作用。然而，二甲双胍是否能减轻EGFR-TKI诱导的肺纤维化尚不清楚。采用MTT、Ki 67掺入试验、流式细胞术、免疫染色、Western印迹分析和博来霉素诱导的肺纤维化大鼠模型，在体外和体内检查二甲双胍对EGFR-TKI诱导的肺纤维化加重的影响。我们发现，在肺HFL-1成纤维细胞中，TGF-β或来自TKI处理的肺癌PC-9细胞的条件培养基或来自TKI耐药PC-9 GR细胞的条件培养基诱导了显著的纤维化，如Colony 1a 1和α-肌动蛋白表达增加所示，而二甲双胍抑制了纤维化标志物的表达。此外，二甲双胍降低了TGF-β信号传导的活化，如pSMAD 2和pSMAD 3表达降低所示。在体内，口服吉非替尼加重博莱霉素诱导的大鼠肺纤维化，如HE染色和Masson染色所示。值得注意的是，口服二甲双胍联合给药可抑制吉非替尼引起的博来霉素诱导的肺纤维化加重。我们已经证明二甲双胍可减轻吉非替尼诱导的TGF-β或博来霉素诱导的肺纤维化恶化。这些观察结果表明二甲双胍可与EGFR-TKI联合治疗NSCLC患者。
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.