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

Abstract

Simple Summary Irinotecan is a widely used chemotherapy drug for colorectal cancer, but overcoming resistance to irinotecan remains a significant challenge. FL118, a drug similar to irinotecan, has shown promise as a new treatment option. FL118 functions by reducing the levels of a protein called survivin, which, in turn, decreases the expression of RAD51, a key protein involved in DNA repair. FL118 has been demonstrated to reduce cancer cell viability and overcome irinotecan resistance in colorectal cancer cells, suggesting it could serve as an effective treatment following irinotecan.Abstract 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.