학술논문
2-Methoxyestradiol reduces radiation-induced skin damage and organ fibrosis
Document Type
Dissertation/ Thesis
Author
Source
Subject
Language
English
Abstract
Radiation-induced skin injury (RISI) is a main side effect of radiotherapy for cancer patients, with vascular damage being a common pathogenesis of acute and chronic RISI. Despite the severity of RISI, there are few treatments for it that are in clinical use. 2-Methoxyestradiol (2-ME) has been reported to regulate the radiation-induced vascular endothelial-to-mesenchymal transition. Thus, it was investigated 2-ME as a potent anti-cancer and hypoxia-inducible factor 1 alpha (HIF-1α) inhibitor drug that prevents RISI by targeting HIF-1α. 2-ME treatment prior to and post irradiation inhibited RISI on the skin of C57/BL6 mice. 2-ME also reduced radiation-induced inflammation, skin thickness, and vascular fibrosis. In particular, post-treatment with 2-ME after irradiation repaired the damaged vessels on the irradiated dermal skin, inhibiting endothelial HIF-1α expression. In addition to the increase in vascular density, post-treatment with 2-ME showed fibrotic changes in residual vessels with SMA+CD31+ on the irradiated skin. Furthermore, 2-ME significantly inhibited fibrotic changes and accumulated DNA damage in irradiated human dermal microvascular endothelial cells. Therefore, I suggest that 2-ME may be a potent therapeutic agent for RISI.
Radiation-induced fibrosis of normal tissues is known to be a major side effect in patients receiving radiation therapy and thus there are many studies have investigated how to treat it. It has been reported that the drug 2-Methoxyestradiol (2-ME) inhibits the endothelial-to-mesenchymal transition (EndMT) of radiation-induced tissue fibrosis and 2-ME prevents fibrosis by modulating radiation-induced EndMT. For improvement of the 2-ME’s efficacy, it was co-administered with the CHIR-9902, and radiation-induced fibrosis was used as a therapeutic strategy. CHIR-99021 is a glycogen synthesis kinase (GSK) inhibitor, and when GSK is inhibited, the expressions of fibronectin, collagen 1a, and a-SMA all decreased. Therefore, it was confirmed that when 2-ME and CHIR-99021 were co-administered, lung and liver fibrosis was inhibited compared to each drug being administered alone. In addition, it was also confirmed that the fibrosis stage was regulated in the transgenic mice when 2-ME and CHIR-99021 were co-administered. This suggests that with 2-ME can be combined with CHIR-99021 and used as a fibrotic disease inhibitor.
Radiation-induced fibrosis of normal tissues is known to be a major side effect in patients receiving radiation therapy and thus there are many studies have investigated how to treat it. It has been reported that the drug 2-Methoxyestradiol (2-ME) inhibits the endothelial-to-mesenchymal transition (EndMT) of radiation-induced tissue fibrosis and 2-ME prevents fibrosis by modulating radiation-induced EndMT. For improvement of the 2-ME’s efficacy, it was co-administered with the CHIR-9902, and radiation-induced fibrosis was used as a therapeutic strategy. CHIR-99021 is a glycogen synthesis kinase (GSK) inhibitor, and when GSK is inhibited, the expressions of fibronectin, collagen 1a, and a-SMA all decreased. Therefore, it was confirmed that when 2-ME and CHIR-99021 were co-administered, lung and liver fibrosis was inhibited compared to each drug being administered alone. In addition, it was also confirmed that the fibrosis stage was regulated in the transgenic mice when 2-ME and CHIR-99021 were co-administered. This suggests that with 2-ME can be combined with CHIR-99021 and used as a fibrotic disease inhibitor.