Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth.

Abstract

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.

• Authors: Huafeng Zhang, David Z Qian, Yee Sun Tan, Kangae Lee, Ping Gao, Yunzhao R Ren, Sergio Rey, Hans Hammers, Daniel Chang, Roberto Pili, Chi V Dang, Jun O Liu, Gregg L Semenza
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 50 Pg. 19579-86 (Dec 16 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 19020076 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Basic Helix-Loop-Helix Transcription Factors
• Cardiac Glycosides
• Hypoxia-Inducible Factor 1, alpha Subunit
• endothelial PAS domain-containing protein 1
• Digoxin
• Luciferases, Firefly

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Basic Helix-Loop-Helix Transcription Factors (antagonists & inhibitors, biosynthesis, genetics)
• Cardiac Glycosides (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Digoxin (pharmacology)
• Genes, Reporter (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, biosynthesis, genetics)
• Luciferases, Firefly (genetics)
• Mice
• Mice, SCID
• Protein Biosynthesis (drug effects)
• Transcription, Genetic (drug effects)
• Transfection
• Xenograft Model Antitumor Assays