Hellebrin and its aglycone form hellebrigenin display similar in vitro growth inhibitory effects in cancer cells and binding profiles to the alpha subunits of the Na+/K+-ATPase

Molecular Cancer

Research

Steven Karlish¹  Elena Ainbinder¹  Adriana Katz¹  Daniel M. Tal¹  Ernst Urban²  Walter Berger³  Walter Miklos³  Martin Zehl⁴  Brigitte Kopp⁴  Alessio Cimmino⁵  Antonio Evidente⁵  Robert Kiss⁶  Laetitia Moreno Y Banuls⁶  Olivier Feron⁷ 

[1] Department of Biological Chemistry, Weizmann Institute of Science, 76100, Rehovot, Israel;Department of Medicinal Chemistry, University of Vienna, 1090, Vienna, Austria;Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria;Department of Pharmacognosy, University of Vienna, 1090, Vienna, Austria;Dipartimento di Scienze Chimiche, Complesso Universitario Monte Sant’Angelo, Università di Napoli Federico II, 80126, Napoli, Italy;Laboratoire de Toxicologie; Faculté de Pharmacie, Université Libre de Bruxelles (ULB), 1050, Brussels, Belgium;Pole of Pharmacology & Therapeutics (UCL-FATH), Angiogenesis & Cancer Research Laboratory, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium;

关键词: Cardiotonic steroids;    Cardenolides;    Bufadienolides;    Cancer;    Glycoside / aglycone forms;    Lactate release - oxygen consumption;   

DOI  :  10.1186/1476-4598-12-33

 received in 2012-11-04, accepted in 2013-04-17,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundSurface-expressed Na+/K+-ATPase (NaK) has been suggested to function as a non-canonical cardiotonic steroid-binding receptor that activates multiple signaling cascades, especially in cancer cells. By contrast, the current study establishes a clear correlation between the IC50in vitro growth inhibitory concentration in human cancer cells and the Ki for the inhibition of activity of purified human α1β1 NaK.MethodsThe in vitro growth inhibitory effects of seven cardiac glycosides including five cardenolides (ouabain, digoxin, digitoxin, gitoxin, uzarigenin-rhamnoside, and their respective aglycone forms) and two bufadienolides (gamabufotalin-rhamnoside and hellebrin, and their respective aglycone forms) were determined by means of the MTT colorimetric assay and hellebrigenin-induced cytotoxic effects were visualized by means of quantitative videomicroscopy. The binding affinity of ten of the 14 compounds under study was determined with respect to human α1β1, α2β1 and α3β1 NaK complexes. Lactate releases and oxygen consumption rates were also determined in cancer cells treated with these various cardiac glycosides.ResultsAlthough cardiotonic steroid aglycones usually display weaker binding affinity and in vitro anticancer activity than the corresponding glycoside, the current study demonstrates that the hellebrin / hellebrigenin pair is at odds with respect to this rule. In addition, while some cardiac steroid glycosides (e.g., digoxin), but not the aglycones, display a higher binding affinity for the α2β1 and α3β1 than for the α1β1 complex, both hellebrin and its aglycone hellebrigenin display ~2-fold higher binding affinity for α1β1 than for the α2β1 and α3β1 complexes. Finally, the current study highlights a common feature for all cardiotonic steroids analyzed here, namely a dramatic reduction in the oxygen consumption rate in cardenolide- and bufadienolide-treated cells, reflecting a direct impact on mitochondrial oxidative phosphorylation.ConclusionsAltogether, these data show that the binding affinity of the bufadienolides and cardenolides under study is usually higher for the α2β1 and α3β1 than for the α1β1 NaK complex, excepted for hellebrin and its aglycone form, hellebrigenin, with hellebrigenin being as potent as hellebrin in inhibiting in vitro cancer cell growth.

【 授权许可】

Unknown   
© Moreno Y Banuls et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.