ReferenceID 3566
Therapeutic concentrations of digitoxin inhibit endothelial focal adhesion kinase and angiogenesis induced by different growth factors
Br J Pharmacol
BACKGROUND AND PURPOSE: Cardiac glycosides are Na+ /K+ -ATPases inhibitors used to treat congestive heart failure and cardiac arrhythmias. Epidemiological studies indicate that patients on digitalis therapy are more prot
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Record Fields
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- Reference Id
- 3566
- Evidence Id
- 20156
- Core Evidence Id
- 20156
- Source Reference Id
- 434
- Herb2 Reference Id
- HBREF000754
- Subject Paper Key
- HBIN023784_28688145
- Pubmed Id
- 28688145
- Doi
- 10.1111/bph.13944
- Paper Title
- Therapeutic concentrations of digitoxin inhibit endothelial focal adhesion kinase and angiogenesis induced by different growth factors
- Paper Abstract
- BACKGROUND AND PURPOSE: Cardiac glycosides are Na+ /K+ -ATPases inhibitors used to treat congestive heart failure and cardiac arrhythmias. Epidemiological studies indicate that patients on digitalis therapy are more protected from cancer. Evidence of a selective cytotoxicity against cancer cells has suggested their potential use as anticancer drugs. The effect on angiogenesis of clinically used cardiac glycosides has not been extensively explored. EXPERIMENTAL APPROACH: We studied the effect of digoxin, digitoxin and ouabain on early events of the angiogenic process in HUVECs. We determined HUVEC viability, proliferation, migration and differentiation into capillary tube-like structures. We also tested drug activity using an in vivo angiogenesis model. Activation of protein tyrosine kinase 2 (FAK) and signalling proteins associated with the Na+ /K+ -ATPase signalosome was determined by Western blotting. KEY RESULTS: Digitoxin and ouabain (1-100 nM) inhibited HUVEC migration, concentration-dependently, without affecting cell viability, while digoxin induced apoptosis at the same concentrations. Digitoxin antagonized growth factor-induced migration and tubularization at concentrations (1-25 nM) within its plasma therapeutic range. The anti-angiogenic effect of digitoxin was confirmed also by in vivo studies. Digitoxin induced Src, Akt and ERK1/2 phosphorylation but did not affect FAK autophosphorylation at Tyr397 . However, it significantly inhibited growth factor-induced FAK phosphorylation at Tyr576/577 . CONCLUSIONS AND IMPLICATIONS: Therapeutic concentrations of digitoxin inhibited angiogenesis and FAK activation by several pro-angiogenic stimuli. These novel findings suggest a potential repositioning of digitoxin as a broad-spectrum anti-angiogenic drug for diseases where pathological angiogenesis is involved.
- Journal
- Br J Pharmacol
- Publish Year
- 2017
- Experiment Subject
- vivo angiogenesis model
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Pathological Angiogenesis
- Paper Title Cn
- Paper Title En
- Therapeutic concentrations of digitoxin inhibit endothelial focal adhesion kinase and angiogenesis induced by different growth factors
- Bilingual Status
- semi_complete