文章：

高通量药物筛选揭示环吡酮胺可诱导胃癌干细胞样细胞形成

High-Throughput Drug Screening Revealed That Ciclopirox Olamine Can Engender Gastric Cancer Stem-like Cells

原文发布日期：3 September 2023

DOI: 10.3390/cancers15174406

类型: Article

开放获取: 是

英文摘要：

Cancer stem cells (CSCs) are relevant therapeutic targets for cancer treatment. Still, the molecular circuits behind CSC characteristics are not fully understood. The low number of CSCs can sometimes be an obstacle to carrying out assays that explore their properties. Thus, increasing CSC numbers via small molecule-mediated cellular reprogramming appears to be a valid alternative tool. Using the SORE6-GFP reporter system embedded in gastric non-CSCs (SORE6−), we performed a high-throughput image-based drug screen with 1200 small molecules to identify compounds capable of converting SORE6− to SORE6+ (CSCs). Here, we report that the antifungal agent ciclopirox olamine (CPX), a potential candidate for drug repurposing in cancer treatment, is able to reprogram gastric non-CSCs into cancer stem-like cells via activation of SOX2 expression and increased expression of C-MYC, HIF-1α, KLF4, and HMGA1. This reprogramming depends on the CPX concentration and treatment duration. CPX can also induce cellular senescence and the metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis. We also disclose that the mechanism underlying the cellular reprogramming is similar to that of cobalt chloride (CoCl2), a hypoxia-mimetic agent.

摘要翻译： 

癌症干细胞（CSCs）是癌症治疗的重要靶点。然而，其特性背后的分子调控机制尚未完全阐明。CSCs数量稀少有时会成为探索其特性的实验障碍。因此，通过小分子介导的细胞重编程增加CSCs数量成为一种有效的替代策略。本研究利用嵌入胃癌非干细胞（SORE6−）的SORE6-GFP报告系统，对1200种小分子化合物进行高通量成像筛选，以鉴定能将SORE6−转化为SORE6+（CSCs）的化合物。我们发现抗真菌药物环吡酮胺（CPX）——一种具有癌症治疗药物再利用潜力的候选化合物——能够通过激活SOX2表达并上调C-MYC、HIF-1α、KLF4和HMGA1的表达，将胃癌非干细胞重编程为癌症干细胞样细胞。这种重编程效应具有浓度和时间依赖性。CPX还能诱导细胞衰老，并使细胞代谢从氧化磷酸化（OXPHOS）向糖酵解转变。我们进一步揭示，该细胞重编程机制与缺氧模拟剂氯化钴（CoCl2）的作用机理相似。

原文链接：

High-Throughput Drug Screening Revealed That Ciclopirox Olamine Can Engender Gastric Cancer Stem-like Cells