文章：

FL118通过下调Survivin–RAD51抑制同源重组修复通路增强结直肠癌治疗效果

FL118 Enhances Therapeutic Efficacy in Colorectal Cancer by Inhibiting the Homologous Recombination Repair Pathway through Survivin–RAD51 Downregulation

原文发布日期：3 October 2024

DOI: 10.3390/cancers16193385

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: Irinotecan, a camptothecin (CPT) derivative, is commonly used as a first-line therapy for colorectal cancer (CRC), but resistance remains a significant challenge. This study aims to explore the therapeutic potential of FL118, another CPT derivative, with a focus on overcoming resistance to irinotecan.Methods:The effects of FL118 on CRC cells were evaluated, and bioinformatics analysis was performed on RNA-seq data. Transfection was conducted to observe the knockdown effect of survivin, and the in vivo efficacy of FL118 was assessed using a xenograft model.Results: FL118 induces apoptosis, G2/M arrest, and DNA damage. A notable mechanism of action of FL118 is a reduction in survivin levels, which downregulates the expression of RAD51, a key marker of homologous recombination, and attenuates DNA repair processes. Given that SN38 is the active metabolite of irinotecan, FL118 reduces cell viability and RAD51 in SN38-resistant LOVO cells.Conclusions: Our findings provide effective insights into the antitumor activity of FL118 and its potential as a therapeutic agent for overcoming irinotecan resistance in CRC.

摘要翻译： 

背景/目的：伊立替康作为一种喜树碱衍生物，常被用作结直肠癌的一线治疗药物，但其耐药性仍是重大挑战。本研究旨在探讨另一种喜树碱衍生物FL118的治疗潜力，重点关注其克服伊立替康耐药性的能力。方法：评估FL118对结直肠癌细胞的作用，并对RNA测序数据进行生物信息学分析。通过转染实验观察survivin的敲低效应，并利用异种移植模型评估FL118的体内疗效。结果：FL118可诱导细胞凋亡、G2/M期阻滞和DNA损伤。FL118的一个显著作用机制是降低survivin水平，从而下调同源重组关键标志物RAD51的表达，并减弱DNA修复过程。鉴于SN38是伊立替康的活性代谢物，FL118在SN38耐药的LOVO细胞中能降低细胞活力和RAD51水平。结论：本研究为FL118的抗肿瘤活性及其作为克服结直肠癌伊立替康耐药性治疗药物的潜力提供了有效见解。

原文链接：

FL118 Enhances Therapeutic Efficacy in Colorectal Cancer by Inhibiting the Homologous Recombination Repair Pathway through Survivin–RAD51 Downregulation