Alzahrani Shiekhah Mohammad, Al Doghaither Huda Abdulaziz, Alkhatabi Hind Ali, Basabrain Mohammad Abdullah, Pushparaj Peter Natesan
Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah P.O. Box 21589, Saudi Arabia.
Institute of Genomic Medicine Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah P.O. Box 21589, Saudi Arabia.
Cancers (Basel). 2025 Apr 27;17(9):1470. doi: 10.3390/cancers17091470.
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).
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.
The combination index showed that HT-29 cells were the most responsive to the combined treatment, even with , (V600E), and mutations. 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.
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 the (V600E) mutation showed promising findings in this study.
背景/目的：结直肠癌（CRC）是一个重大的全球健康问题，其发病率和死亡率不断上升。在肿瘤学领域，药物重新利用已成为一种与传统治疗相结合的有前景的治疗策略。本研究旨在评估β受体阻滞剂普萘洛尔（PRO）作为单一疗法以及与卡培他滨（CAP）联合使用时治疗结直肠癌细胞系（HCT - 116和HT - 29）的潜力。
评估单一疗法和联合疗法对结直肠癌细胞活力、联合指数、形态和细胞死亡诱导的影响。使用RNA测序对HT - 29细胞进行转录组分析。进行代谢物谱分析，并使用流式细胞术和生化分析评估生化参数的变化。
联合指数表明，即使存在 、 （V600E）和 突变，HT - 29细胞对联合治疗的反应最为敏感。此外，与对照组相比，HT - 29联合组的铁死亡被协同激活。此外，我们观察到HT - 29联合组中氧化磷酸化代谢物增加，同时细胞内和线粒体活性氧升高、线粒体膜电位破坏以及丙二醛（MDA）水平升高，这些都是铁死亡的特征。此外，RNA测序数据表明，铁死亡诱导与坏死性凋亡相关。联合疗法抑制细胞迁移并增强HT - 29细胞的免疫反应。
这些发现表明，PRO作为与CAP联合治疗CRC的潜在辅助疗法具有前景。在本研究中，只有具有 （V600E）突变的HT - 29细胞显示出有前景的结果。
