Background/Objectives: Colorectal cancer (CRC) is a significant global health issue with rising incidence and mortality rates. In oncology, drug repurposing has emerged as a promising therapeutic strategy in conjunction with conventional treatments. This study aimed to evaluate the potential of repurposing propranolol (PRO), a beta blocker, for the treatment of CRC cell lines (HCT-116 and HT-29), both as a monotherapy and in combination with capecitabine (CAP). Methods: Effects of mono- and combination therapies on viability, combination index, morphology, and cell death induction of CRC cells were assessed. Transcriptome analysis of HT-29 cells was performed using RNA sequencing. Metabolite profiling was conducted, and changes in biochemical parameters were evaluated using flow cytometry and biochemical analyses. Results: The combination index showed that HT-29 cells were the most responsive to the combined treatment, even withPIK3CA,B-RAF(V600E), andTP53mutations. Moreover, ferroptosis was synergistically activated in the combined group of HT-29 in comparison to control. Furthermore, we observed an increase in OXPHOS metabolites, along with elevated intracellular and mitochondrial ROS, disruption of mitochondrial membrane potential, and greater levels of malondialdehyde (MDA) in the HT-29 combined group, which are the features of ferroptosis. Furthermore, ferroptosis induction was coupled with necroptosis, as indicated by RNA-sequencing data. Combination therapy inhibited cell migration and enhanced the immune response of HT-29 cells. Conclusions: These findings suggest that PRO is promising as a potential adjuvant therapy in combination with CAP for the treatment of CRC. Only HT-29 cells with theB-RAF(V600E) mutation showed promising findings in this study.
背景/目的：结直肠癌（CRC）是一个重大的全球性健康问题，其发病率和死亡率呈上升趋势。在肿瘤学领域，药物再利用已成为与传统治疗相结合的一种有前景的治疗策略。本研究旨在评估将β受体阻滞剂普萘洛尔（PRO）重新用于治疗CRC细胞系（HCT-116和HT-29）的潜力，包括其作为单一疗法以及与卡培他滨（CAP）联合使用的效果。方法：评估了单一疗法和联合疗法对CRC细胞活力、联合指数、形态以及细胞死亡诱导的影响。使用RNA测序对HT-29细胞进行了转录组分析。进行了代谢物分析，并使用流式细胞术和生化分析评估了生化参数的变化。结果：联合指数显示，HT-29细胞对联合治疗的反应最为敏感，即使存在PIK3CA、B-RAF(V600E)和TP53突变。此外，与对照组相比，HT-29联合治疗组的铁死亡被协同激活。进一步观察发现，HT-29联合治疗组的氧化磷酸化代谢物增加，同时细胞内和线粒体活性氧水平升高，线粒体膜电位受损，丙二醛（MDA）水平更高，这些都是铁死亡的特征。此外，RNA测序数据表明，铁死亡的诱导与坏死性凋亡同时发生。联合疗法抑制了细胞迁移并增强了HT-29细胞的免疫反应。结论：这些发现表明，PRO与CAP联合治疗CRC具有作为潜在辅助疗法的前景。在本研究中，仅携带B-RAF(V600E)突变的HT-29细胞显示出有希望的结果。
肿瘤(癌症)患者之家