2-Methoxyestradiol Inhibits Radiation-Induced Skin Injuries

• Published in: International journal of molecular sciences Vol. 23; no. 8; p. 4171
• Main Authors: Kim, Ji-Hee, Nam, Jae-Kyung, Kim, A-Ram, Park, Min-Sik, Lee, Hae-June, Park, Joonho, Kim, Joon, Lee, Yoon-Jin
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10-04-2022; MDPI
• Subjects: 2-Methoxyestradiol; 2-Methoxyestradiol - pharmacology; Animals; Apoptosis; Chemical compounds; Collagen; DNA damage; Drug dosages; Endothelial Cells; Endothelium; Erythema; Fibrosis; Growth factors; HIF 1-α; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-inducible factor 1a; Inflammation; Injuries; Mercaptoethanol; Mesenchyme; Mice; Microvasculature; Oral administration; Pathogenesis; Pharmacology; Pulmonary fibrosis; Radiation damage; Radiation effects; Radiation injuries; Radiation Injuries - drug therapy; Radiation Injuries - etiology; Radiation therapy; radiation-induced skin injury; Skin; Skin injuries; vascular fibrosis; 2-Methoxyestradiol; radiation-induced skin injury; HIF 1-α; vascular fibrosis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23084171

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, we 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, we suggest that 2-ME may be a potent therapeutic agent for RISI.