The First Affiliated Hospital of Zhengzhou University, 1 Longhu Middle Ring Road, Zhengzhou, Jinshui District, Henan Province, People's Republic of China.
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, People's Republic of China.
Pulm Pharmacol Ther. 2023 Jun;80:102202. doi: 10.1016/j.pupt.2023.102202. Epub 2023 Mar 10.
Pulmonary fibrosis is a chronic interstitial fibrosis lung disease with high mortality, which is often complicated with lung cancer. The incidence of IPF complicated with lung cancer is getting higher and higher. At present, there is no consensus on the management and treatment of pulmonary fibrosis patients with lung cancer. There is an urgent need to develop preclinical drug evaluation methods for IPF with lung cancer and potential therapeutic drugs for IPF with lung cancer. The pathogenic mechanism of IPF is similar to that of lung cancer, and the multi-effect drugs with anticancer and anti-fibrosis will have potential value in the treatment of IPF complicated with lung cancer. In this study, we established an animal model of IPF complicated with lung cancer in situ to evaluate the therapeutic effect of the antiangiogenic drug anlotinib. The pharmacodynamic results in vivo showed that anlotinib could significantly improve the lung function of IPF-LC mice, reduce the content of collagen in lung tissue, increase the survival rate of mice, and inhibit the growth of lung tumor in mice. The results of Western blot and immunohistochemical analysis of lung tissue showed that anlotinib significantly inhibited the expression of fibrosis marker protein α-SMA, Collagen I and Fibronectin and tumor proliferation marker protein PCNA in mouse lung tissue, and down-regulated the content of serum tumor marker CEA. Through transcriptome analysis, we found that anlotinib regulates MAPK signal pathway, PARP signal pathway and coagulation cascade signal pathway in lung cancer and pulmonary fibrosis, which all play an important role in lung cancer and pulmonary fibrosis. In addition, there is crosstalk between the signal pathway participated by the target of anlotinib and MAPK, JAK/STAT and mTOR signal pathway. In summary, anlotinib will be a candidate for IPF-LC treatment.
肺纤维化是一种高死亡率的慢性间质性肺纤维化疾病，常合并肺癌。特发性肺纤维化（IPF）合并肺癌的发病率越来越高，目前对于肺纤维化合并肺癌患者的管理和治疗尚缺乏共识，迫切需要开发针对合并肺癌的 IPF 的临床前药物评价方法和潜在的治疗药物。IPF 的发病机制与肺癌相似，具有抗癌和抗纤维化多效作用的药物在治疗合并肺癌的 IPF 中具有潜在价值。本研究建立了原位肺纤维化合并肺癌动物模型，评估抗血管生成药物安罗替尼的治疗效果。体内药效学结果表明，安罗替尼能显著改善 IPF-LC 小鼠的肺功能，减少肺组织胶原含量，提高小鼠的生存率，抑制小鼠肺部肿瘤的生长。肺组织 Western blot 和免疫组化分析结果表明，安罗替尼能显著抑制小鼠肺组织中纤维化标志物蛋白 α-SMA、Collagen I 和 Fibronectin 及肿瘤增殖标志物蛋白 PCNA 的表达，下调血清肿瘤标志物 CEA 的含量。通过转录组分析，我们发现安罗替尼调控肺癌和肺纤维化中 MAPK 信号通路、PARP 信号通路和凝血级联信号通路，这些通路在肺癌和肺纤维化中均发挥重要作用。此外，安罗替尼的作用靶点参与的信号通路与 MAPK、JAK/STAT 和 mTOR 信号通路之间存在相互作用。综上所述，安罗替尼将是治疗 IPF-LC 的候选药物。
