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

Huafeng Zhang, David Z. Qian, Yee Sun Tan, Kang Ae 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

    427 Scopus citations

    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

    Keywords

    • Cancer therapy
    • Hypoxia
    • Tumor xenograft

    ASJC Scopus subject areas

    • General

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  • Cite this

    Zhang, H., Qian, D. Z., Tan, Y. S., Lee, K. A., Gao, P., Ren, Y. R., Rey, S., Hammers, H., Chang, D., Pili, R., Dang, C. V., Liu, J. O., & Semenza, G. L. (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, 105(50), 19579-19586. https://doi.org/10.1073/pnas.0809763105