Digitalis: Its Mode of Action, Receptor, and Structure–Activity Relationships

Thomas, Richard; Gray, Peter; Andrews, Joanne

doi:10.1016/b978-0-12-013319-2.50009-7

Cited by 59 publications

(78 citation statements)

References 378 publications

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“…Of note, at higher concentrations of the CGs or longer periods of incubation, the CGs directly induced cell death, consistent with previous reports (23,24). Compared with the human isoform, CGs bind the a1 subunit of murine Na + /K + -ATPase with less affinity, thereby rendering murine cells resistant to any effects of CGs that are mediated through this ATPase (25,26). Consistent with this prediction, the tested CGs did not block L-PHA-induced cell death nor agglutination of MDAY-D2 murine leukemia cells (data not shown), suggesting that CGs inhibition of L-PHA toxicity to Jurkat cells requires its known function as inhibitors of human Na + /K + -ATPase.…”

Section: Resultssupporting

confidence: 77%

Inhibition of the Sodium/Potassium ATPase Impairs N-Glycan Expression and Function

et al. 2008

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Aberrant N-linked glycans promote the malignant potential of cells by enhancing the epithelial-to-mesenchymal transition and the invasive phenotype. To identify small molecule inhibitors of N-glycan biosynthesis, we developed a chemical screen based on the ability of the tetravalent plant lectin L-phytohemagglutinin (L-PHA) to bind and crosslink surface glycoproteins with B1,6GlcNAc-branched complex type N-glycans and thereby induce agglutination and cell death. In this screen, Jurkat cells were treated with a library of offpatent chemicals (n = 1,280) to identify molecules that blocked L-PHA-induced death. The most potent hit from this screen was the cardiac glycoside (CG) dihydroouabain. In secondary assays, a panel of CGs was tested for their effects on L-PHAinduced agglutination and cell death. All of the CGs tested inhibited L-PHA-induced death in Jurkat cells, and the most potent CG tested was digoxin with an EC 50 of 60 F 20 nmol/L. Digoxin also increased the fraction of some concanavalin A-binding N-glycans. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, digoxin specifically increased GlcNAc 1 Man 3 GlcNAc 2 Fuc 1 and GlcNAc 2 Man 3 GlcNAc 2 Fuc 1 oligosaccharides demonstrating an impairment of the N-glycan pathway. Consistent with this effect on the N-glycan pathway, digoxin inhibited N-glycosylation-mediated processes of tumor cell migration and invasion. Furthermore, digoxin prevented distant tumor formation in two mouse models of metastatic prostate cancer. Thus, taken together, our high throughput screen identified CGs as modifiers of the N-glycan pathway. These molecules can be used as tools to better understand the role of N-glycans in normal and malignant cells. Moreover, these results may partly explain the anticancer effect of CGs in cardiovascular patients. [Cancer Res 2008;68(16):6688-97]

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Section: Resultssupporting

confidence: 77%

Inhibition of the Sodium/Potassium ATPase Impairs N-Glycan Expression and Function

et al. 2008

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“…From this screen, we identified a family of cardiac glycosides, two of which, digoxin and digitoxin are used to treat patients with congestive heart failure and cardiac arrhythmias (32). These compounds exert a positive inotropic effect on the heart due to their ability to inhibit the Na + /K + ATPase pump which leads to a concomitant increase in intracellular calcium (33).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Sodium Potassium Adenosine Triphosphatase Pump Sensitizes Cancer Cells to Anoikis and Prevents Distant Tumor Formation

Simpson

Mawji²,

Anyiwe³

et al. 2009

Cancer Research

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Normal epithelial cells undergo apoptosis upon detachment from the extracellular matrix, a process termed ''anoikis.'' However, malignant epithelial cells with metastatic potential resist anoikis and can survive in an anchorage-independent fashion. Molecules that sensitize resistant cells to anoikis will be useful chemical probes to understand this pathway. To identify novel anoikis sensitizers in anoikis-resistant PPC-1 prostate adenocarcinoma cells, a library of 2,000 off-patent drugs and natural products was screened for their ability to preferentially induce cell death in suspension over adherent culture conditions. This screen identified five members of the family of cardiac glycosides as anoikis sensitizers, including ouabain, peruvoside, digoxin, digitoxin, and strophanthidin. We conducted further studies with ouabain to discern the mechanism of cardiac glycoside-induced anoikis sensitization. Ouabain initiated anoikis through the mitochondrial pathway of caspase activation. In addition, ouabain sensitized cells to anoikis by inhibiting its known target, the Na + /K + ATPase pump, and inducing hypoosmotic stress. Resistance to anoikis permits cancer cells to survive in the circulation and facilitates their metastasis to distant organs, so we tested the effects of Na + /K + ATPase inhibition on distant tumor formation in mouse models. In these mouse models, ouabain inhibited tumor metastases but did not alter the growth of subcutaneous tumors. Thus, we have identified a novel mechanism to sensitize resistant cells to anoikis and decrease tumor metastasis. These results suggest a potential mechanism for the observed clinical reduction in metastasis and relapse in breast cancer patients who have undergone treatments with cardiac glycosides.

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“…The Na,K-ATPase is the pharmacological target for the cardiac glycoside class of drugs, such as digitoxin, which is used in the treatment of congestive heart failure and certain arrhythmias (5,6). Defining the residues involved in the binding of these drugs will aid in our understanding of their inhibition mechanism.…”

mentioning

confidence: 99%

Ouabain Interactions with the H5-H6 Hairpin of the Na,K-ATPase Reveal a Possible Inhibition Mechanism via the Cation Binding Domain

Palasis

Kuntzweiler

Argüello

et al. 1996

Journal of Biological Chemistry

101

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Digitalis: Its Mode of Action, Receptor, and Structure–Activity Relationships

Cited by 59 publications

References 378 publications

Inhibition of the Sodium/Potassium ATPase Impairs N-Glycan Expression and Function

Inhibition of the Sodium/Potassium ATPase Impairs N-Glycan Expression and Function

Inhibition of the Sodium Potassium Adenosine Triphosphatase Pump Sensitizes Cancer Cells to Anoikis and Prevents Distant Tumor Formation

Ouabain Interactions with the H5-H6 Hairpin of the Na,K-ATPase Reveal a Possible Inhibition Mechanism via the Cation Binding Domain

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