BACKGROUND Esophageal cancer is one of the most common malignant tumors in the world. With currently available therapies, only 20% ~ 30% patients can survive this disease for more than 5 years. TRAIL, a natural ligand for death receptors that can induce the apoptosis of cancer cells, has been explored as a therapeutic agent for cancers, but it has been reported that many cancer cells are resistant to TRAIL, limiting the potential clinical use of TRAIL as a cancer therapy. Meanwhile, Periplocin (CPP), a natural compound from dry root of Periploca sepium Bge, has been studied for its anti-cancer activity in a variety of cancers. It is not clear whether CPP and TRAIL can have activity on esophageal squamous cell carcinoma (ESCC) cells, or whether the combination of these two agents can have synergistic activity. METHODS We used MTS assay, flow cytometry and TUNEL assay to detect the effects of CPP alone or in combination with TRAIL on ESCC cells. The mechanism of CPP enhances the activity of TRAIL was analyzed by western blot, dual luciferase reporter gene assay and chromatin immunoprecipitation (ChIP) assay. The anti-tumor effects and the potential toxic side effects of CPP alone or in combination with TRAIL were also evaluated in vivo. RESULTS In our studies, we found that CPP alone or in combination with TRAIL could inhibit the proliferation of ESCC cells and induce apoptosis, and we certificated that combination of two agents exert synergized functions. For the first time, we identified FoxP3 as a key transcriptional repressor for both DR4 and DR5. By down-regulating FoxP3, CPP increases the expression of DR4/DR5 and renders ESCC cells much more sensitive to TRAIL. We also showed that CPP reduced the expression of Survivin by inhibiting the activity of Wnt/β-catenin pathway. All these contributed to synergistic activity of CPP and TRAIL on ESCC cells in vitro and in vivo. CONCLUSION Our data suggest that CPP and TRAIL could be further explored as potential therapeutic approach for esophageal cancer.

中文翻译：

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天然化合物 Periplocin 和 TRAIL 的组合在体外和体内诱导食管鳞状细胞癌凋亡：抗癌治疗的意义。

背景技术食管癌是世界上最常见的恶性肿瘤之一。根据目前可用的治疗方法，只有20%~30%的患者能够存活5年以上。TRAIL是死亡受体的天然配体，可以诱导癌细胞凋亡，已被探索作为癌症的治疗剂，但据报道，许多癌细胞对TRAIL具有抗性，限制了TRAIL作为癌症治疗剂的潜在临床应用。癌症治疗。同时，Periplocin (CPP) 是一种来自 Periploca sepium Bge 干燥根的天然化合物，已研究其在多种癌症中的抗癌活性。目前尚不清楚 CPP 和 TRAIL 是否对食管鳞状细胞癌 (ESCC) 细胞具有活性，或者这两种药物的组合是否可以具有协同活性。方法采用MTS法、流式细胞术和TUNEL法检测CPP单独或联合TRAIL对ESCC细胞的影响。通过蛋白质印迹、双荧光素酶报告基因测定和染色质免疫沉淀（ChIP）测定分析CPP增强TRAIL活性的机制。还评估了CPP单独或与TRAIL联合使用的抗肿瘤作用和潜在的毒副作用。结果在我们的研究中，我们发现CPP单独或与TRAIL联合可以抑制ESCC细胞的增殖并诱导细胞凋亡，并且我们证明两种药物的组合发挥协同作用。我们首次确定 FoxP3 是 DR4 和 DR5 的关键转录抑制因子。通过下调 FoxP3，CPP 增加 DR4/DR5 的表达，并使 ESCC 细胞对 TRAIL 更加敏感。我们还表明，CPP 通过抑制 Wnt/β-catenin 通路的活性来降低 Survivin 的表达。所有这些都有助于 CPP 和 TRAIL 在体外和体内对 ESCC 细胞的协同活性。结论 我们的数据表明，CPP 和 TRAIL 可以作为食管癌的潜在治疗方法进行进一步探索。