LETTER
Digoxin, HIF-1, and cance
In a ecen issue o PNAS, Zhang e al. (1) ind ha digoxin
inhibi s HIF-1 (a ansc ip ion ac o highly in ol ed in cance
de elopmen ) and sugges ha his e ec migh be obse ed
in pa ien s aking his d ug. They also epo ha digoxin
blocks umo g ow h in mice (1). These da a sugges ha
digoxin has an icance po en ial.
The au ho s obse e ha digoxin inhibi s HIF-1 a 100 nM
and discuss ha he he apeu ic plasma concen a ions o
digoxin in ca diac pa ien s a e ⬇10–30 nM (1). Ex ensi e
clinical use o digoxin has shown ha he he apeu ic plasma
concen a ions o his d ug a e 1.6 ⫾1.0 nM and ha highe
concen a ions induce oxici y because o i s na ow he apeu-
ic window (2). These da a do no suppo he idea o HIF-1
being inhibi ed in pa ien s ea ed wi h digoxin.
I has been known o some ime ha mouse cells a e ⬎100
imes mo e esis an han human cells o he e ec s o
digoxin and o he ca diac glycosides (3). This means ha he
an icance e ec s induced by digoxin in mice ha bo ing hu-
man malignan cells (1) a e p obably due o in e species di -
e ences in sensi i i y and no o selec i e inhibi ion o umo
cells. Acco dingly, unlike digi oxin, e idence sugges s ha
digoxin does no inhibi he g ow h o cance cells selec i ely
(4, 5).
In b ie , Zhang e al. (1) demons a e ha ca diac glyco-
sides a e a new class o HIF-1 inhibi o s. Howe e , i seems
unlikely ha digoxin inhibi s HIF-1 a he apeu ic concen a-
ions o ha he an icance e ec s ha hey obse ed in mice
a e ele an in humans.
Miguel Lopez-Laza o
1
Depa men o Pha macology, Facul y o Pha macy, Uni e si y o
Se ille, Se ille 41011, Spain
1. Zhang H, e al. (2008) Digoxin and o he ca diac glycosides inhibi HIF-1
␣
syn hesis and
block umo g ow h. P oc Na l Acad Sci USA 105:19579–19586.
2. Ho nes am B, Je ling M, Ka lsson MO, Held P (2003) In a enously adminis e ed
digoxin in pa ien s wi h acu e a ial ib illa ion: A popula ion pha macokine ic/
pha macodynamic analysis based on he Digi alis in Acu e A ial Fib illa ion ial. Eu
J Clin Pha macol 58:747–755.
3. Gup a RS, Chop a A, S e sko DK (1986) Cellula basis o he species di e ences in
sensi i i y o ca diac glycosides (digi alis). J Cell Physiol 127:197–206.
4. Lopez-Laza o M, e al. (2005) Digi oxin inhibi s he g ow h o cance cell lines a
concen a ions commonly ound in ca diac pa ien s. J Na P od 68:1642–1645.
5. Lopez-Laza o M (2007) Digi oxin as an an icance agen wi h selec i i y o cance cells:
Possible mechanisms in ol ed. Expe Opin The Ta ge s 11:1043–1053.
Au ho con ibu ions: M.L.-L. w o e he pape .
The au ho decla es no con lic o in e es .
1E-mail: [email p o ec ed].
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PNAS
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Ma ch 3, 2009
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ol. 106
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no. 9 www.pnas.o g兾cgi兾doi兾10.1073兾pnas.0813047106