Digoxin and other cardiac glycosides inhibit HIF-1α 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 μM. Eleven of these drugs were cardiac glycosides, including digoxin, ouabain, and p...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2008-12, Vol.105 (50), p.19579-19586
Hauptverfasser: Zhang, Huafeng, Qian, David Z, 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
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container_end_page 19586
container_issue 50
container_start_page 19579
container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 105
creator Zhang, Huafeng
Qian, David Z
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
description 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.
doi_str_mv 10.1073/pnas.0809763105
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source Jstor Complete Legacy; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry
subjects Biological Sciences
Cancer
Cardiac glycosides
Cell growth
Cultured cells
Heterologous transplantation
Hypoxia
Messenger RNA
Protein synthesis
Tumors
Vehicles
title Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth
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