Abstract
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.
Highlights
Radiotherapy plays an important role in the treatment of thoracic malignancies including esophageal cancer, breast cancer and non-small cell lung cancer
We evaluated the radioprotective effects of a small-molecule inhibitor of bromodomain and extra terminal (BET) bromodomains, JQ1 in a rat model and investigated whether its effect was selectively delivered in tumor tissues
Clarifying the underlying mechanisms of radiation-induced lung fibrosis (RILF) is vital for the development of effective strategies
Summary
Radiotherapy plays an important role in the treatment of thoracic malignancies including esophageal cancer, breast cancer and non-small cell lung cancer. Recent studies demonstrated that radiation-induced lung fibrosis is characterized by a tissue repair response triggered by chronic inflammation[10,11,12]. Molecular advances on radiation-induced response and fibrogenesis showed an essential role of epigenetic regulation[16,17]. The BET family proteins, including four members (BRD2, BRD3, BRD4, and bromodomain testis specific protein), are epigenetic reader proteins that recognize acetylated chromatin and involved in regulating gene expressions. These epigenetic readers act as scaffolds and attract components of the transcriptional machinery to these acetylated lysine residues, resulting in modulation of gene transcription[18,19]. The effects of JQ1 on irradiated normal human lung fibroblasts cells and thoracic cancer cells including Eca[109] and MCF7 cells were evaluated
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