Diosmetin enhances the sensitivity of radiotherapy by suppressing homologous recombination in endometrial cancer
Diosmetin enhances the sensitivity of radiotherapy by suppressing homologous recombination in endometrial cancer
复制标题
香叶素通过抑制子宫内膜癌的同源重组来增强放疗的敏感性。
DOI：
10.1080/15384101.2020.1831257
复制
发表时间：
2020-10-17
期刊：
影响因子：
4.3
通讯作者：
Wan, Xiaoping
中科院分区：
文献类型：
--
作者：
Hu, Zhiyi;Cai, Bailian;Wan, Xiaoping
放射治疗是子宫内膜癌（EC）的基本治疗方法，特别是在晚期，转移和复发病例中。结合放射治疗，主要导致DNA双链断裂（DSB），与小分子靶向异常激活的同源重组（HR）修复途径，具有治疗晚期EC的巨大潜力。在这里，我们证明了薯蓣皂苷（DIO），一种天然黄酮类化合物，抑制HR，从而抑制细胞增殖，提高EC对放射治疗的敏感性。克隆形成实验表明，DIO和X射线相结合显着抑制EC细胞的活力相比，单独用薯蓣皂苷或X射线处理的细胞。当结合0.4戈伊X射线和4 μ M DIO时，EC细胞的存活分数下降至40%;然而，单独的每种治疗仅分别导致约15%和22%的癌细胞死亡。进一步的机制研究表明，薯蓣皂苷抑制招募RPA 2和RAD 51，参与HR修复途径的两个关键因素，发生DSB。因此，我们建议，薯蓣皂苷和放射线的组合是一个有前途的治疗策略，用于治疗子宫内膜癌。
Radiotherapy is an essential treatment for endometrial cancer (EC), especially in advanced, metastatic, and recurrent cases. Combining radiotherapy, which mainly causes DNA double-strand breaks (DSBs), with small molecules targeting aberrantly activated homologous recombination (HR) repair pathways holds great potential for treating ECs in advanced stages. Here, we demonstrate that diosmetin (DIO), a natural flavonoid, suppresses HR, therefore inhibiting cell proliferation and enhancing the sensitivity of EC to radiotherapy. Clonogenic experiments revealed that combining DIO and X-ray significantly inhibited the viability of EC cells compared to cells treated with diosmetin or X-ray alone. The survival fraction of EC cells decreased to 40% when combining 0.4 Gy X-ray and 4 mu M DIO; however, each treatment alone only caused death in approximately 15% and 22% of cancer cells, respectively. Further mechanistic studies showed that diosmetin inhibited the recruitment of RPA2 and RAD51, two critical factors involved in the HR repair pathway, upon the occurrence of DSBs. Thus, we propose that a combination of diosmetin and irradiation is a promising therapeutic strategy for treating endometrial cancer.