Abstract
Radiotherapy is a common treatment for cancer patients, but its use is often restricted by the tolerance of normal tissue. As cancer patients live longer, delayed radiation effects on normal tissue have become a concern. Radiation-induced enteropathy, including inflammatory bowel disease and fibrosis, are major issues for long-term cancer survivors. To investigate whether silibinin attenuates delayed radiation-induced intestinal injury in mice, we focused on intestinal fibrotic changes. Silibinin improved delayed radiation injuries in mice in association with decreased collagen deposition within the intestines and deceased transforming growth factor (TGF)-β1 levels in the intestine and plasma. Treating mice bearing CT26 mouse colon cancer tumors with both silibinin and radiation stimulated tumor regression more than radiation alone. We also investigated the effect of silibinin on the radiation-induced epithelial-to-mesenchymal transition (EMT), the primary mechanism of fibrosis. We assessed changes in E-cadherin, N-cadherin, and α-smooth muscle actin expression, and demonstrated that silibinin attenuates radiation-induced EMT. Irradiating intestinal epithelial cells increased TGF-β1 levels, but silibinin suppressed TGF-β1 expression by inhibiting Smad2/3 phosphorylation. These results suggest silibinin has the potential to serve as a useful therapeutic agent in patients with radiation-induced intestinal fibrosis.
Highlights
While radiation therapy is the most widely used cancer treatment, over 60% of patients who receive pelvic or abdominal therapy exhibit acute bowel toxicity
To investigate silibinin’s intestinal effects, we exposed the abdomens of mice to 13 Gy of ionizing radiation (IR) under anesthesia using an X-RAD 320 X-ray system at a dose rate of 2 Gy/min
We investigated whether transforming growth factor (TGF)-β1 participates in delayed radiation enteropathy by performing real-time qRT-PCR for intestinal TGF-β1 in each group (n = 6) at 200 days after IR
Summary
While radiation therapy is the most widely used cancer treatment, over 60% of patients who receive pelvic or abdominal therapy exhibit acute bowel toxicity. Extensive intestinal resection can manage small bowel injury because limited surgical treatment of chronic radiation enteritis is associated with high late mortalities and high complication rates [3]. Late intestinal toxicity always evolves into a chronic woundhealing process typically associated with mesenchymal cell hyperplasia and activation, tissue disorganization, and fibrillar collagen deposition [4]. Several fibrogenic and inflammatory cytokines, including TGF-β1, promote late radiation injury [5,6,7,8]. Preventative strategies and novel therapies for radiation enteritis have not reduced the need for surgical intervention [9, 10]
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