Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 3, 166 28 Prague 6, Czech Republic.
Department of Pharmacology, Second Faculty of Medicine, Charles University, Plzeňská 311, 150 00 Prague, Czech Republic.
Molecules. 2021 Mar 28;26(7):1905. doi: 10.3390/molecules26071905.
Maintenance of Na and K gradients across the cell plasma membrane is an essential process for mammalian cell survival. An enzyme responsible for this process, sodium-potassium ATPase (NKA), has been currently extensively studied as a potential anticancer target, especially in lung cancer and glioblastoma. To date, many NKA inhibitors, mainly of natural origin from the family of cardiac steroids (CSs), have been reported and extensively studied. Interestingly, upon CS binding to NKA at nontoxic doses, the role of NKA as a receptor is activated and intracellular signaling is triggered, upon which cancer cell death occurs, which lies in the expression of different NKA isoforms than in healthy cells. Two major CSs, digoxin and digitoxin, originally used for the treatment of cardiac arrhythmias, are also being tested for another indication-cancer. Such drug repositioning has a big advantage in smoother approval processes. Besides this, novel CS derivatives with improved performance are being developed and evaluated in combination therapy. This article deals with the NKA structure, mechanism of action, activity modulation, and its most important inhibitors, some of which could serve not only as a powerful tool to combat cancer, but also help to decipher the so-far poorly understood NKA regulation.
维持哺乳动物细胞质膜内外钠离子和钾离子梯度是细胞存活的必要过程。一种负责该过程的酶，钠钾三磷酸腺苷酶（NKA），目前已被广泛研究作为一种潜在的抗癌靶点，尤其是在肺癌和神经胶质瘤中。迄今为止，已经报道并广泛研究了许多 NKA 抑制剂，主要来源于甾体类化合物（CSs）家族的天然产物。有趣的是，CS 以非毒性剂量与 NKA 结合后，NKA 作为受体的作用被激活并触发细胞内信号转导，从而导致癌细胞死亡，这与健康细胞中不同的 NKA 同工型表达有关。最初用于治疗心律失常的两种主要的 CS，地高辛和洋地黄毒苷，也正在进行另一种适应症——癌症的测试。这种药物重新定位在审批流程上具有很大的优势。除此之外，还在开发和评估具有改进性能的新型 CS 衍生物的联合治疗。本文讨论了 NKA 的结构、作用机制、活性调节及其最重要的抑制剂，其中一些不仅可以作为对抗癌症的有力工具，还有助于破解迄今为止了解甚少的 NKA 调节。
