Department of Medicine, School of Medicine, Joseph E Walther Hall, Indiana University, 980 W. Walnut St, C560, R3-C560, Indianapolis, IN, 46202, USA.
Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
Cell Mol Life Sci. 2023 Aug 16;80(9):250. doi: 10.1007/s00018-023-04910-9.
Cardiac glycosides (CGs) are a class of bioactive organic compounds well-known for their application in treating heart disease despite a narrow therapeutic window. Considerable evidence has demonstrated the potential to repurpose CGs for cancer treatment. Chemical modification of these CGs has been utilized in attempts to increase their anti-cancer properties; however, this has met limited success as their mechanism of action is still speculative. Recent studies have identified the DNA damage response (DDR) pathway as a target of CGs. DDR serves to coordinate numerous cellular pathways to initiate cell cycle arrest, promote DNA repair, regulate replication fork firing and protection, or induce apoptosis to avoid the survival of cells with DNA damage or cells carrying mutations. Understanding the modus operandi of cardiac glycosides will provide critical information to better address improvements in potency, reduced toxicity, and the potential to overcome drug resistance. This review summarizes recent scientific findings of the molecular mechanisms of cardiac glycosides affecting the DDR signaling pathway in cancer therapeutics from 2010 to 2022. We focus on the structural and functional differences of CGs toward identifying the critical features for DDR targeting of these agents.
强心苷（CGs）是一类生物活性有机化合物，以其在治疗心脏病方面的应用而闻名，尽管其治疗窗口很窄。大量证据表明，将 CGs 重新用于癌症治疗具有潜力。人们尝试通过化学修饰这些 CGs 来提高其抗癌特性；然而，由于其作用机制仍在推测之中，这种方法的效果有限。最近的研究已经确定 DNA 损伤反应（DDR）途径是 CGs 的一个靶点。DDR 协调众多细胞途径以启动细胞周期停滞、促进 DNA 修复、调节复制叉启动和保护、或诱导细胞凋亡，以避免具有 DNA 损伤或携带突变的细胞的存活。了解强心苷的作用方式将为提高效力、降低毒性以及克服耐药性提供关键信息。本综述总结了 2010 年至 2022 年期间强心苷影响癌症治疗中 DDR 信号通路的分子机制的最新科学发现。我们专注于 CGs 的结构和功能差异，以确定这些药物靶向 DDR 的关键特征。
