Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth.
A library of drugs that are in clinical trials or use was screened for inhibitors of hypoxia-inducible factor 1 (HIF-1). Twenty drugs inhibited HIF-1-dependent gene transcription by >88% at a concentration of 0.4 microM. Eleven of these drugs were cardiac glycosides, including digoxin, ouabain, and proscillaridin A, which inhibited HIF-1alpha protein synthesis and expression of HIF-1 target genes in cancer cells. Digoxin administration increased latency and decreased growth of tumor xenografts, whereas treatment of established tumors resulted in growth arrest within one week. Enforced expression of HIF-1alpha by transfection was not inhibited by digoxin, and xenografts derived from these cells were resistant to the anti-tumor effects of digoxin, demonstrating that HIF-1 is a critical target of digoxin for cancer therapy.
Zhang
Huafeng
H
Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Qian
David Z
DZ
Tan
Yee Sun
YS
Lee
Kangae
K
Gao
Ping
P
Ren
Yunzhao R
YR
Rey
Sergio
S
Hammers
Hans
H
Chang
Daniel
D
Pili
Roberto
R
Dang
Chi V
CV
Liu
Jun O
JO
Semenza
Gregg L
GL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D002301:Cardiac Glycosides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004077:Digoxin / Q000494:pharmacology*; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D049409:Luciferases, Firefly / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D014176:Protein Biosynthesis / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D002301:Cardiac Glycosides; D004077:Digoxin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D049409:Luciferases, Firefly; D000099162:Endothelial PAS Domain-Containing Protein 1