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Therapeutic concentrations of digitoxin inhibit endothelial focal adhesion kinase and angiogenesis induced by diverse growth factors.

Therapeutic concentrations of digitoxin inhibit endothelial focal adhesion kinase and angiogenesis induced by diverse growth factors.
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Trenti A, Zulato E, Pasqualini L, Indraccolo S, Bolego C, Trevisi L,


Trenti A, Zulato E, Pasqualini L, Indraccolo S, Bolego C, Trevisi L, (click to view)

Trenti A, Zulato E, Pasqualini L, Indraccolo S, Bolego C, Trevisi L,

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British journal of pharmacology 2017 07 08() doi 10.1111/bph.13944
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 human umbilical vein endothelial cells (HUVEC). 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 to Na(+) /K(+) -ATPase signalosome was determined by western blotting.

KEY RESULTS
Digitoxin and ouabain (1-100 nM) inhibited HUVEC migration in a concentration-dependent manner 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 antiangiogenic 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 Tyr 576/577.

CONCLUSIONS AND IMPLICATIONS
Our results show that therapeutic concentrations of digitoxin inhibit angiogenesis and FAK activation by diverse pro-angiogenic stimuli. These novel findings suggest a potential repositioning of digitoxin as a broad-spectrum antiangiogenic drug for diseases where pathological angiogenesis is involved.

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