The mechanistic role of cardiac glycosides in DNA damage response and repair signaling.
The mechanistic role of cardiac glycosides in DNA damage response and repair signaling.
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DOI：
10.1007/s00018-023-04910-9
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发表时间：
2023-08-16
影响因子：
8
通讯作者：
Turchi, John J.
中科院分区：
文献类型：
--
作者：
Ainembabazi, Diana;Zhang, Youwei;Turchi, John J.
强心苷（CGs）是一类生物活性有机化合物，因其在治疗心脏病方面的应用而闻名，尽管其治疗窗口较窄。大量证据表明，强心苷有可能被重新用于癌症治疗。对这些强心苷进行化学修饰曾被用于尝试增强其抗癌特性；然而，由于其作用机制仍不确定，这一尝试取得的成功有限。最近的研究已确定DNA损伤应答（DDR）通路是强心苷的一个作用靶点。DDR用于协调众多细胞通路，以启动细胞周期阻滞、促进DNA修复、调控复制叉的启动和保护，或诱导细胞凋亡，从而避免DNA受损的细胞或携带突变的细胞存活。了解强心苷的作用方式将为更好地解决效力提高、毒性降低以及克服耐药性的潜力等问题提供关键信息。本综述总结了2010年至2022年强心苷在癌症治疗中影响DDR信号通路的分子机制的最新科学发现。我们关注强心苷在结构和功能上的差异，以确定这些药物靶向DDR的关键特征。
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.
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