Liu Huilin, Huang Chao, Liu Zhenni, Li Yuhan, Zhu Yanan, Gao Min, Chen Jing, Zhang Hui, Xiao Zhengtao, Zhao Wei
Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Institute of Molecular and Translational Medicine (IMTM), Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
Br J Pharmacol. 2025 Mar;182(6):1275-1291. doi: 10.1111/bph.17405. Epub 2024 Dec 1.
Cardiac glycosides (CGs), traditionally prescribed for heart failure and arrhythmias, show anticancer potential. However, their mechanisms for preferential inhibition of tumour tissue and constituent malignant cells are not fully elucidated. This study aims to elucidate the therapeutic benefits of CGs in targeting specific tumours and dissect their multi-targeting mechanisms that confer their cytotoxicity against malignant cells.
We designed an integrated workflow to identify therapeutic CGs with high toxicity to certain cancers, investigating their multi-target effects, assessing their toxicity to malignant cells and analysing the prognostic relevance of CGs' target genes. The computational findings were confirmed through gene knockdown, cell viability assays, reactive oxygen species (ROS) measurements and so forth.
CGs modulate multiple genes crucial for ion homeostasis, oxidative stress and apoptosis, with a particularly strong inhibitory effects on uveal melanoma (UVM). Notably, digitoxin suppresses UVM cell proliferation and induces ROS levels by simultaneously targeting STAT3 and KLF5. Single-cell transcriptomic analysis revealed that malignant cells are likely more vulnerable to CGs due to their higher expression of CG target genes compared with surrounding cells in the UVM microenvironment.
Given UVM's limited options, our study highlights the potential of digitoxin as a promising novel therapeutic agent for this aggressive and rare ocular cancer. Our comprehensive approach is effective in identifying the potent, cancer-specific therapeutic agents from herbal plants.
传统上用于治疗心力衰竭和心律失常的强心苷显示出抗癌潜力。然而，它们优先抑制肿瘤组织和组成恶性细胞的机制尚未完全阐明。本研究旨在阐明强心苷在靶向特定肿瘤方面的治疗益处，并剖析其赋予对恶性细胞细胞毒性的多靶向机制。
我们设计了一个综合工作流程，以鉴定对某些癌症具有高毒性的治疗性强心苷，研究它们的多靶点效应，评估它们对恶性细胞的毒性，并分析强心苷靶基因的预后相关性。通过基因敲低、细胞活力测定、活性氧（ROS）测量等方法对计算结果进行了验证。
强心苷调节多个对离子稳态、氧化应激和细胞凋亡至关重要的基因，对葡萄膜黑色素瘤（UVM）具有特别强的抑制作用。值得注意的是，洋地黄毒苷通过同时靶向STAT3和KLF5来抑制UVM细胞增殖并诱导ROS水平。单细胞转录组分析表明，与UVM微环境中的周围细胞相比，恶性细胞可能由于其更高的强心苷靶基因表达而更容易受到强心苷的影响。
鉴于UVM的治疗选择有限，我们的研究突出了洋地黄毒苷作为这种侵袭性罕见眼部癌症的一种有前景的新型治疗药物的潜力。我们的综合方法有效地从草药植物中鉴定出了有效的、癌症特异性治疗药物。
