文章：

罗米地辛通过DDIT4-mTORC1通路发挥抗食管鳞状细胞癌活性

Romidepsin exhibits anti-esophageal squamous cell carcinoma activity through the DDIT4-mTORC1 pathway 

原文发布日期：2024-03-13 

英文摘要：

Esophageal squamous cell carcinoma (ESCC) is one of the most common human malignancies worldwide and is associated with high morbidity and mortality. Current treatment options are limited, highlighting the need for development of novel effective agents. Here, a high-throughput drug screening (HTS) was performed using ESCC cell lines in both two- and three-dimensional culture systems to screen compounds that have anti-ESCC activity. Our screen identified romidepsin, a histone deactylase inhibitor, as a potential anti-ESCC agent. Romidepsin treatment decreased cell viability, induced apoptosis and cell cycle arrest in ESCC cell lines, and these findings were confirmed in ESCC cell line-derived xenografted (CDX) mouse models. Mechanically, romidepsin induced transcriptional upregulation of DNA damage-inducible transcript 4 (DDIT4) gene by histone hyperacetylation at its promoter region, leading to the inhibition of mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, romidepsin exhibited better efficacy and safety compared to the conventional therapeutic drugs in ESCC patient-derived xenografted (PDX) mouse models. These data indicate that romidepsin may be a novel option for anti-ESCC therapy. 

摘要翻译： 

食管鳞状细胞癌（ESCC）是全球最常见的人类恶性肿瘤之一，具有高发病率和高死亡率的特点。目前治疗方案有限，这凸显了开发新型有效药物的迫切需求。本研究采用二维和三维培养系统对ESCC细胞系进行高通量药物筛选（HTS），以筛选具有抗ESCC活性的化合物。我们的筛选发现组蛋白去乙酰化酶抑制剂罗米地辛是一种潜在的抗ESCC药物。罗米地辛处理可降低ESCC细胞系的细胞活力，诱导细胞凋亡和细胞周期阻滞，这些发现在ESCC细胞系衍生移植瘤（CDX）小鼠模型中得到证实。从机制上讲，罗米地辛通过其启动子区域组蛋白高度乙酰化，诱导DNA损伤诱导转录本4（DDIT4）基因的转录上调，从而抑制哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）通路。此外，在ESCC患者来源移植瘤（PDX）小鼠模型中，罗米地辛相比传统治疗药物展现出更好的疗效和安全性。这些数据表明罗米地辛可能成为抗ESCC治疗的新选择。

原文链接：

Romidepsin exhibits anti-esophageal squamous cell carcinoma activity through the DDIT4-mTORC1 pathway