2-Methoxyestradiol Inhibits Radiation-Induced Skin Injuries

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, 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.

2‐Methoxyestradiol inhibits the proliferation level in keloid fibroblasts through p38 in the MAPK/Erk signaling pathway

“…In addition, 2ME2 may also show therapeutic effect in dermatology. Kim's study showed that 2ME2 may be a potent therapeutic agent for radiation‐induced skin injury by reducing radiation‐induced inflammation, skin thickness, and vascular fibrosis 25 . Tang also concluded that 2ME2 showed satisfying treatment effect for psoriasis in vivo and in vitro 26 .…”

“…In this case, 2ME2 showed satisfying treating effect toward keloid fibroblasts with low drug concentration, which may also fibrosis. 25 Tang also concluded that 2ME2 showed satisfying treatment effect for psoriasis in vivo and in vitro. 26 Clinical trials have also focused on 2ME2, such as prostate cancer, 27 breast cancer, 28 and multiple myeloma.…”

Tissue fibrosis induced by radiotherapy: current understanding of the molecular mechanisms, diagnosis and therapeutic advances

“…In comparison to treatment after recovery from irradiation, prophylactic treatment with transdermal DFO has been found to be more effective in decreasing levels of markers of ROS and apoptosis, improving tissue perfusion, and mitigating radiation-induced skin fibrosis [ 358 ]. Another HIF-1α inhibitor, 2-Methoxyestradiol (2-ME), which is a metabolite of estradiol, has been approved as an anti-cancer drug that inhibits tubulin polymerization [ 359 ]. In a study conducted on irradiated mice, it was found that 2-ME had positive effects on radiation-induced pulmonary injury and fibrosis.…”

2-Methoxyestradiol-3,17-O,O-bis-sulfamate (STX140) Inhibits Proliferation and Invasion via Senescence Pathway Induction in Human BRAFi-Resistant Melanoma Cells

“…Our previous study reported that 2-ME activity can induce cell death, it acts as an antiangiogenic compound and as a senescence inductor [17]. In addition, other studies showed that 2-ME also reversed metabolic-related pro-carcinogenic phenotype in osteosarcoma cells [18], inhibited skin injuries induced by radiation exposure [19], increased the infiltration of cytotoxic CD8+ T lymphocytes and the expression of PD-L1 in B16 tumors, in which authors suggest enhancing the efficacy of PD-1 blockade immunotherapy [20]. However, despite promising results, 2-ME has shown limited application due to its poor oral bioavailability (<2%) and extensive bioconjugation in vivo [21,22].…”