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

Huafeng Zhang, Zheng (David) 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

Research output: Contribution to journalArticle

397 Citations (Scopus)

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 μM. Eleven of these drugs were cardiac glycosides, including digoxin, ouabain, and proscillaridin A, which inhibited HIF-1α 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-1α 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.

Original languageEnglish (US)
Pages (from-to)19579-19586
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number50
DOIs
StatePublished - Dec 16 2008
Externally publishedYes

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Hypoxia-Inducible Factor 1
Cardiac Glycosides
Digoxin
Growth
Neoplasms
Heterografts
Proscillaridin
Pharmaceutical Preparations
Neoplasm Genes
Ouabain
Transfection
Clinical Trials
Genes
Proteins

Keywords

  • Cancer therapy
  • Hypoxia
  • Tumor xenograft

ASJC Scopus subject areas

  • General

Cite this

Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth. / Zhang, Huafeng; Qian, Zheng (David); Tan, Yee Sun; Lee, KangAe; Gao, Ping; Ren, Yunzhao R.; Rey, Sergio; Hammers, Hans; Chang, Daniel; Pili, Roberto; Dang, Chi V.; Liu, Jun O.; Semenza, Gregg L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 50, 16.12.2008, p. 19579-19586.

Research output: Contribution to journalArticle

Zhang, H, Qian, ZD, Tan, YS, Lee, K, Gao, P, Ren, YR, Rey, S, Hammers, H, Chang, D, Pili, R, Dang, CV, Liu, JO & Semenza, GL 2008, 'Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 50, pp. 19579-19586. https://doi.org/10.1073/pnas.0809763105
Zhang, Huafeng ; Qian, Zheng (David) ; Tan, Yee Sun ; Lee, KangAe ; Gao, Ping ; Ren, Yunzhao R. ; Rey, Sergio ; Hammers, Hans ; Chang, Daniel ; Pili, Roberto ; Dang, Chi V. ; Liu, Jun O. ; Semenza, Gregg L. / Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 50. pp. 19579-19586.
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