Cardiac glycosides decrease prostate specific antigen expression by down-regulation of prostate derived Ets factor.
OBJECTIVE
While cardiac glycosides are the mainstay of congestive heart failure treatment, early studies showed that pharmacological doses of cardiac glycosides inhibited prostate cancer cell line proliferation. We evaluated the mechanisms of cardiac glycosides, including digoxin, digitoxin and ouabain (Sigma®), on prostate specific antigen gene expression in vitro.


METHODS
We cultured LNCaP cells (ATCC®) and used them to determine the effect of cardiac glycosides on prostate derived Ets factor and prostate specific antigen expression. We determined prostate derived Ets factor and prostate specific antigen expression by reverse transcription-polymerase chain reaction, immunoblot, transient gene expression assay or enzyme-linked immunosorbent assay.


RESULTS
Noncytotoxic doses (100 nM) of cardiac glycosides for 24 hours inhibited prostate specific antigen secretion by LNCaP cells. Reverse transcriptase-polymerase chain reaction and immunoblot revealed that cardiac glycosides significantly down-regulated prostate specific antigen and prostate derived Ets factor expression. Transient gene expression assays showed that prostate derived Ets factor over expression enhanced prostate specific antigen promoter activity. However, prostate specific antigen and prostate derived Ets factor gene promoter activity was attenuated when LNCaP cells were treated with 100 nM cardiac glycosides. When LNCaP cells were treated with 25 nM digitoxin or digoxin for 60 hours, prostate specific antigen secretion decreased by 30%.


CONCLUSIONS
Results suggest that cardiac glycoside inhibition of prostate specific antigen gene expression may be caused by the down-regulation of prostate derived Ets factor gene expression. When cells were chronically treated with digoxin or digitoxin at concentrations close to or at therapeutic plasma levels, prostate specific antigen secretion decreased. This phenomenon merits further study to determine whether it occurs in men on cardiac glycoside therapy.
Juang
Horng-Heng
HH
Department of Anatomy, Chang Gung University, Kwei-Shan, Taiwan, Republic of China.
Lin
Yu-Fen
YF
Chang
Phei-Lang
PL
Tsui
Ke-Hung
KH
D002301:Cardiac Glycosides / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004074:Digitoxin / Q000494:pharmacology*; D004077:Digoxin / Q000494:pharmacology*; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D010042:Ouabain / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D050783:Proto-Oncogene Proteins c-ets / Q000187:drug effects* / Q000502:physiology*; D014407:Tumor Cells, Cultured
D002301:Cardiac Glycosides; D002316:Cardiotonic Agents; D050783:Proto-Oncogene Proteins c-ets; C403974:SPDEF protein, human; D010042:Ouabain; D004077:Digoxin; D004074:Digitoxin; D017430:Prostate-Specific Antigen