Na+/K+ ATPase Inhibitors in Cancer
Na+/K+ ATPase Inhibitors in Cancer
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DOI：
10.2174/1389450115666140908125025
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发表时间：
2014-01-01
影响因子：
3.2
通讯作者：
Stournaras, Christos
中科院分区：
文献类型：
--
作者：
Alevizopoulos, Konstantinos;Calogeropoulou, Theodora;Stournaras, Christos
钠钾泵（Na+/K+ ATPase）是一种存在于所有高等真核生物中的跨膜蛋白复合物，是维持细胞内离子和渗透压平衡的关键能量消耗泵。近年来，Na+/K+ ATP酶抑制剂被认为是各种信号的重要转换器和/或整合器，以及形成具有信号传导特性的受体复合物的蛋白质-蛋白质相互作用支架，其最突出的药理学作用是在诸如充血性心力衰竭的病理条件下增加心肌收缩性。因此，自1975年以来，地高辛等Na+/K+ ATP酶调节剂已获得监管机构批准，并广泛用于心力衰竭的治疗。从早期观察到服用地高辛的心脏病患者癌症发病率降低开始，最近的流行病学和其他研究已经巩固了Na+/K+ ATP酶抑制剂在前列腺癌、乳腺癌、肺癌或白血病等适应症中的抗癌潜力。更重要的是，一系列新的优化的Na+/K+ ATP酶抑制剂最近在多项临床前试验中显示出很强的抗癌活性，并已进入早期临床试验。总之，这些结果表明，Na+/K+ ATP酶是一个新兴的癌症靶点，值得进一步研究。在这篇综述中，我们总结了与癌细胞选择性高度相关的酶的关键功能特性，回顾了Na+/K+ ATP酶抑制剂的最突出的化学类别，并分析了它们的下游效应物。此外，我们还讨论了这些候选药物在成为癌症患者新的有效治疗方法方面的总体发展前景。
Sodium potassium pump (Na+/K+ ATPase) is a transmembrane protein complex found in all higher eukaryotes acting as a key energy-consuming pump maintaining ionic and osmotic balance in cells. Recently recognized as an important transducer and/or integrator of various signals as well as a protein-protein interaction scaffold forming receptor complexes with signaling properties, the most prominent pharmacological role of Na+/K+ ATPase inhibitors is the increase of myocardial contractility in pathologic conditions such as congestive heart failure. Consequently, modulators of Na+/K+ ATPase such as digoxin have been approved by regulatory authorities and are widely used in the treatment of cardiac failure since 1975. Initiating from early observations of reduction of cancer incidence in cardiac patients taking digoxin, recent epidemiological and other studies have consolidated the anti-cancer potential of Na+/K+ ATPase inhibitors in indications such as prostate, breast, lung cancer or leukemia. More importantly, a new series of pharmacologically optimized Na+/K+ ATPase inhibitors has recently shown strong anti-cancer activities in multiple preclinical assays and have reached early clinical trials. Altogether, these results suggest that Na+/K+ ATPase is an emerging cancer target that merits further investigation. In this review, we summarize key functional properties of the enzyme that are highly relevant for cancer cell selectivity, review the most prominent chemical classes of Na+/K+ ATPase inhibitors and analyze their downstream effectors. Moreover, we discuss overall development prospects of these candidate drugs on their way to becoming new effective treatments of cancer in patients.