Digoxin, HIF-1, and cancer

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]. E26 兩 PNAS 兩 Ma ch 3, 2009 兩 ol. 106 兩 no. 9 www.pnas.o g兾cgi兾doi兾10.1073兾pnas.0813047106