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

被引:510
|
作者
Zhang, Huafeng [1 ,2 ]
Qian, David Z. [1 ,2 ]
Tan, Yee Sun [1 ,3 ]
Lee, KangAe [1 ,3 ]
Gao, Ping [4 ]
Ren, Yunzhao R. [5 ]
Rey, Sergio [1 ,3 ]
Hammer, Hans [2 ]
Chang, Daniel [1 ,4 ]
Pili, Roberto [2 ]
Dang, Chi V. [2 ]
Liu, Jun O. [5 ]
Semenza, Gregg L. [1 ,2 ,3 ,4 ,6 ,7 ]
机构
[1] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Vasc Program, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA
[5] Johns Hopkins Univ, Sch Med, Dept Pharmacol, Baltimore, MD 21205 USA
[6] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA
[7] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Baltimore, MD 21205 USA
关键词
cancer therapy; hypoxia; tumor xenograft;
D O I
10.1073/pnas.0809763105
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 mu M. Eleven of these drugs were cardiac glycosides, including digoxin, ouabain, and proscillaridin A, which inhibited HIF-1 alpha 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-1 alpha 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.
引用
收藏
页码:19579 / 19586
页数:8
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