Pharmacological targeting of BET proteins attenuates radiation-induced lung fibrosis

• Published in: Scientific reports Vol. 8; no. 1; pp. 998 - 10
• Main Authors: Wang, Jian, Zhou, Fangzheng, Li, Zhenyu, Mei, Hong, Wang, Ye, Ma, Hong, Shi, Liangliang, Huang, Ai, Zhang, Tao, Lin, Zhenyu, Wu, Gang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.01.2018; Nature Publishing Group
• Subjects: 13; 13/1; 14/19; 14/34; 14/63; 631/67/1059/485; 692/700/565/2194; 82/1; 82/29; 82/51; 82/80; Animal models; Animals; Azepines - pharmacology; Breast cancer; c-Myc protein; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Collagen (type I); Collagen Type I - antagonists & inhibitors; Collagen Type I - genetics; Collagen Type I - metabolism; Computed tomography; Esophagus; Female; Fibroblasts; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - radiation effects; Fibrosis; Gamma Rays - adverse effects; Gene Expression Regulation - drug effects; Gene Expression Regulation - radiation effects; Humanities and Social Sciences; Humans; Hydroxyproline; Hydroxyproline - antagonists & inhibitors; Hydroxyproline - biosynthesis; Inflammation; Irradiation; Lung - metabolism; Lung - pathology; Lung - radiation effects; Lung cancer; Lung diseases; MCF-7 Cells; Molecular Targeted Therapy; multidisciplinary; Myc protein; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Proteins - antagonists & inhibitors; Proteins - genetics; Proteins - metabolism; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Pulmonary Fibrosis - etiology; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - pathology; Pulmonary Fibrosis - prevention & control; Radiation; Radiation therapy; Rats; Rats, Sprague-Dawley; Rodents; Science; Science (multidisciplinary); Smad2 protein; Smad2 Protein - antagonists & inhibitors; Smad2 Protein - genetics; Smad2 Protein - metabolism; Smad3 protein; Smad3 Protein - antagonists & inhibitors; Smad3 Protein - genetics; Smad3 Protein - metabolism; Thorax; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Triazoles - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-19343-9

Radiation-induced lung injury has restricted radiotherapy for thoracic cancer. The purpose of this study was to investigate the radioprotective effects of bromodomain and extra terminal (BET) inhibitor JQ1 in a murine model of pulmonary damage. Chest computed tomography (CT) was performed in a rat model after 20 Gy radiation of the right thorax. And histological evaluation and protein expressions of irradiated tissue were analyzed to confirm the potential anti-fibrosis effect of JQ1 and its underlying mechanisms. Moreover, colony formation assays were used to explore the effects of JQ1 on esophageal cancer Eca109 and breast cancer MCF7. JQ1 attenuated radiologic and histologic presentations of radiation-induced fibrosis, inflammatory reaction and pulmonary structural changes and the increase of Hounsfield units (HU) density and hydroxyproline content after radiation. Additionally, JQ1 suppressed BRD4, c-MYC, Collagen I, TGF-β, p-NF-κB p65, p-Smad2 and p-Smad3 expressions after irradiation, repressed proliferation and transdifferentiation of lung fibroblasts, and impaired clonogenic survival of thoracic cancer cells. Collectively, our study demonstrated for the first time that BET Bromodomain inhibitor JQ1 protected normal lung tissue after radiation, and exerted a radiosensitizing effect in thoracic cancer cells.