Zeino Maen, Brenk Ruth, Gruber Lisa, Zehl Martin, Urban Ernst, Kopp Brigitte, Efferth Thomas
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
J Steroid Biochem Mol Biol. 2015 Jun;150:97-111. doi: 10.1016/j.jsbmb.2015.03.008. Epub 2015 Mar 19.
Cardiotonic steroids have long been in clinical use for treatment of heart failure and are now emerging as promising agents in various diseases, especially cancer. Their main target is Na(+)/K(+)-ATPase, a membrane protein involved in cellular ion homeostasis. Na(+)/K(+)-ATPase has been implicated in cancer biology by affecting several cellular events and signaling pathways in both sensitive and drug-resistant cancer cells. Hence, we investigated the cytotoxic activities of 66 cardiotonic steroids and cardiotonic steroid derivatives in sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. Data were then subjected to quantitative structure-activity relationship analysis (QSAR) and molecular docking into Na(+)/K(+)-ATPase, which both indicated a possible differential expression of the pump in the mentioned cell lines. This finding was confirmed by western blotting, intracellular potassium labeling and next generation sequencing which showed that Na(+)/K(+)-ATPase was less expressed in multidrug-resistant than in sensitive cells.
强心甾类药物长期以来一直用于临床治疗心力衰竭，现在正成为治疗各种疾病（尤其是癌症）的有前景的药物。它们的主要靶点是Na(+)/K(+)-ATP酶，这是一种参与细胞离子稳态的膜蛋白。Na(+)/K(+)-ATP酶通过影响敏感和耐药癌细胞中的几种细胞事件和信号通路，与癌症生物学相关。因此，我们研究了66种强心甾类药物和强心甾类衍生物对敏感的CCRF-CEM和多药耐药的CEM/ADR5000白血病细胞的细胞毒性活性。然后对数据进行定量构效关系分析（QSAR）和对Na(+)/K(+)-ATP酶进行分子对接，两者均表明上述细胞系中该泵可能存在差异表达。蛋白质印迹法、细胞内钾标记和下一代测序证实了这一发现，结果显示多药耐药细胞中Na(+)/K(+)-ATP酶的表达低于敏感细胞。
