ABSTRACT

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 μM 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.

摘要

放射治疗是子宫内膜癌 (EC) 的基本治疗方法，尤其是在晚期、转移性和复发病例中。将主要导致 DNA 双链断裂 (DSB) 的放疗与靶向异常激活的同源重组 (HR) 修复途径的小分子相结合，在治疗晚期 ECs 方面具有巨大潜力。在这里，我们证明了天然黄酮类化合物 diosmetin (DIO) 抑制 HR，从而抑制细胞增殖并提高 EC 对放疗的敏感性。克隆实验表明，与单独用洋地黄酮或 X 射线处理的细胞相比，DIO 和 X 射线的组合显着抑制了 EC 细胞的活力。当0.4 Gy X-ray和4 μM DIO结合时，EC细胞的存活率下降到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，在 DSB 发生时，地奥司他汀会抑制 RPA2 和 RAD51（参与 HR 修复途径的两个关键因素）的募集。因此，我们建议将地奥司美汀和辐射相结合是治疗子宫内膜癌的一种有前景的治疗策略。