Abstract
Radiation therapy is the mainstay in the treatment of lung cancer, and lung fibrosis is a radiotherapy-related major side effect that can seriously reduce patient’s quality of life. Nevertheless, effective strategies for protecting against radiation therapy-induced fibrosis have not been developed. Hence, we investigated the radioprotective effects and the underlying mechanism of the standardized herbal extract PM014 on radiation-induced lung fibrosis. Ablative radiation dose of 75 Gy was focally delivered to the left lung of mice. We evaluated the effects of PM014 on radiation-induced lung fibrosis in vivo and in an in vitro model. Lung volume and functional changes were evaluated using the micro-CT and flexiVent system. Fibrosis-related molecules were evaluated by immunohistochemistry, western blot, and real-time PCR. A orthotopic lung tumour mouse model was established using LLC1 cells. Irradiated mice treated with PM014 showed a significant improvement in collagen deposition, normal lung volume, and functional lung parameters, and these therapeutic effects were better than those of amifostine. PM104 attenuated radiation-induced increases in NF-κB activity and inhibited radiation-induced p65 translocation, ROS production, DNA damage, and epithelial-mesenchymal transition. PM104 effectively alleviated fibrosis in an irradiated orthotopic mouse lung tumour model while not attenuating the efficacy of the radiation therapy by reduction of the tumour. Standardized herbal extract PM014 may be a potential therapeutic agent that is able to increase the efficacy of radiotherapy by alleviating radiation-induced lung fibrosis.
Highlights
Radiotherapy is one of the most important treatment strategies for thoracic tumours such as lung cancer, esophageal cancer, and breast cancer
The effect of PM014 on cancer stem cells only suggests the possibility and further research is needed. These results suggest that PM014 treatment in combination with radiotherapy inhibits the fibrosis of normal tissue without interfering with tumour removal and is a promising therapeutic strategy for controlling IR-induced lung fibrosis
To study the radiation-induced damage of normal tissues adjacent to tumours that underwent radiotherapy, we previously established an in vivo mouse model that mimicked clinical S BRT23,24
Summary
Radiotherapy is one of the most important treatment strategies for thoracic tumours such as lung cancer, esophageal cancer, and breast cancer. Suggesting agents that regulate the DNA damage response, apoptosis, and the activation of NF-κB may be effective therapeutic strategies for radiotherapy-induced pulmonary fibrosis. We developed a mouse model that simulates clinical stereotactic body radiotherapy (SBRT) using an image-guided animal irradiation system to deliver a single 75 Gy dose to the mouse lung[8] and validated the induction of lung fibrosis following high-dose IR14. Using this model, in the present study, we focused on the role and mechanism of PM014 in radiation-induced lung fibrosis, and compared its effects to those of amifostine. We investigated the effects of PM014 on preventing fibrosis in normal cells and on inhibiting tumour cells including cancer stem-like cells
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