Abstract
Purpose:
Recent studies suggest a potential application for digoxin in the prevention and/or treatment of prostate cancer. However, the effect of digoxin on androgen receptor (AR)-positive prostate tumor in vivo is not clear. This study is designed to determine if digoxin can inhibit AR-positive xenograft prostate tumors.
Materials and methods:
Athymic male nude mice were utilized to establish subcutaneous C4-2 castration-resistant prostate tumors. The animals were castrated and then treated with daily intraperitoneal (i.p.) injection of digoxin at 2 mg/kg along with vehicle controls for 7 consecutive days. Tumor growth was determined by measuring tumor volume changes, blood vessel density by immunostaining of CD31, and cell proliferation by BrdU labeling. The expression of HIF-1α in C4-2 tumors was measured by Western blot and real-time RT-PCR.
Results:
Digoxin inhibited blood vessel density about fourfold and down-regulated HIF-1α expression at both mRNA and protein levels. However, digoxin did not inhibit C4-2 tumor growth.
Conclusions:
Digoxin is a potent inhibitor of HIF-1α signaling pathway and blood vessel formation in C4-2 castration-resistant prostate tumors.
© 2012 Wiley Periodicals, Inc.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Angiogenesis Inhibitors / administration & dosage
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Digoxin / administration & dosage
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Digoxin / pharmacology*
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Down-Regulation
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Drug Administration Schedule
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Immunohistochemistry
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Injections, Intraperitoneal
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Male
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Mice
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Mice, Nude
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / pathology
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Neovascularization, Pathologic / prevention & control*
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Orchiectomy*
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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Prostatic Neoplasms / blood supply
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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RNA, Messenger / metabolism
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Real-Time Polymerase Chain Reaction
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Receptors, Androgen / metabolism
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Time Factors
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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AR protein, human
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Angiogenesis Inhibitors
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Platelet Endothelial Cell Adhesion Molecule-1
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RNA, Messenger
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Receptors, Androgen
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Digoxin