Radiation resistance and recurrent have become the major factors resulting in poor prognosis in the clinical treatment of patients with nasopharyngeal carcinoma (NPC). New strategies to enhance the efficacy of radiotherapy have been focused on the development of radiosensitizers and searching for directly targets that modulated tumor radiosensitivity. A novel potential radiosensitizer 1,8-Dihydroxy −3-(2′-(4″-methylpiperazin-1″-yl) ethyl-9,10-anthraquinone −3-carboxylate (RP-4) was designed and synthesized based on molecular docking technology, which was expected to regulate the radiosensitivity of tumor cells through targeting Rac1. In order to assess the radiosensitization activity of RP-4 on NPC cells, the highly differentiated CNE1 and poorly differentiated CNE2 cells NPC lines were employed. According to the results, RP-4 showed higher binding affinity toward the interaction with Rac1 than lead compounds. We found that RP-4 could inhibit cell viability and proliferation in CNE1 and CNE2 cells and significantly induced apoptosis after non-toxic concentration of RP-4 combined with 2Gy irradiation. RP-4 could effectively modulated the radiosensitivity both CNE1 cells and CNE2 cells through activating Rac1/NADPH signaling pathway and its downstream JNK/AP-1 pathway. What's more, Rac1/NADPH signaling pathway were significantly activated in Rac1-overexpressed CNE1 and CNE2 cells after treated with RP-4. Taken together, Rac1 and its downstream pathway may probably be the direct targets of RP-4 in regulating radiosensitivity of NPC cells, our finding provided a novel strategy for the development of therapeutic agents in response to tumorous radiation resistance.

放射线抗性和复发已成为导致鼻咽癌（NPC）患者临床治疗不良预后的主要因素。增强放射疗法功效的新策略已集中在放射增敏剂的开发和寻找可调节肿瘤放射敏感性的直接靶标上。设计并合成了一种新型的潜在放射增敏剂1,8-二羟基-3-（2'-（4'-甲基哌嗪-1“-基）乙基-9,10-蒽醌-3-羧酸盐（RP-4）对接技术，有望通过靶向Rac1来调节肿瘤细胞的放射敏感性，为了评估RP-4对NPC细胞的放射敏感性，我们使用了高分化的CNE1和低分化的CNE2细胞NPC系。 ，与铅化合物相比，RP-4对与Rac1的相互作用具有更高的结合亲和力。我们发现，RP-4可以抑制CNE1和CNE2细胞的细胞活力和增殖，并在无毒浓度的RP-4结合2Gy辐射后显着诱导细胞凋亡。RP-4可以通过激活Rac1 / NADPH信号通路及其下游JNK / AP-1通路有效调节CNE1细胞和CNE2细胞的放射敏感性。此外，在用RP-4处理后，Rac1 / NADPH信号通路在Rac1过表达的CNE1和CNE2细胞中被显着激活。两者合计，Rac1及其下游途径可能是调节NPC细胞放射敏感性的RP-4的直接靶点，我们的发现为响应肿瘤抗辐射性的治疗药物的开发提供了新的策略。