title: Digoxin inhibits blood vessel density and HIF-1a expression in castration-resistant C4-2 xenograft prostate tumors.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Bishoy A
authors.initials: BA
authors.lastname: Gayed
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: O'Malley
authors.forename: Jan
authors.initials: J
authors.lastname: Pilch
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004077:Digoxin / Q000008:administration & dosage / Q000494:pharmacology*; D015536:Down-Regulation; D004334:Drug Administration Schedule; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009919:Orchiectomy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D020533:Angiogenesis Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D011944:Receptors, Androgen; D004077:Digoxin