Prostate growth inhibition by subtype-selective alpha(1)-adrenoceptor antagonist naftopidil in benign prostatic hyperplasia.
BACKGROUND
Recently, alpha(1)-adrenoceptors (alpha(1)-ARs) have been reported to play a prominent role in the growth of a variety of cells; however, little is known about prostate growth and subtype-specific effects on cell proliferation. We examined the role of alpha(1d)-AR in prostate growth and the effect of subtype-selective alpha(1)-AR antagonist, naftopidil, which has relatively higher affinity for alpha(1d)-AR, on prostate growth in vitro and in vivo.


METHODS
First, we examined the effect of naftopidil on the cell proliferation of PrEC, PrSC, and PrSMC using WST-1 assay. Second, we performed real-time RT-PCR to quantify each alpha(1)-AR subtype mRNA expression level in a benign prostate hyperplasia (BPH) model rat, which was recently established to pathologically resemble human BPH patients. In addition, naftopidil was given to this model orally for 21 days and the proliferative and apoptotic indexes measured. Third, 18 BPH patients were administered naftopidil for 12 weeks and the proliferative and apoptotic indexes were compared before and after naftopidil administration.


RESULTS
Naftopidil significantly inhibited cell proliferation dose-dependently in all cell lines that expressed alpha(1d)-AR mRNA. The expression level of alpha(1d)-AR during the growth process of the prostate in the BPH model rat was significantly higher than that in the normal prostate (P < 0.001). Naftopidil administration inhibited cell proliferation without apoptosis in the BPH model rat and BPH patients.


CONCLUSIONS
alpha(1d)-AR may play an important role in the regulation of cellular proliferation in the prostate, and alpha(1d)-AR blockage by naftopidil may not only improve lower urinary tract symptoms but also inhibit prostate growth in BPH patients.
Kojima
Yoshiyuki
Y
Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan. ykojima@med.nagoya-cu.ac.jp
Sasaki
Shoichi
S
Oda
Nobuyuki
N
Koshimizu
Taka-Aki
TA
Hayashi
Yutaro
Y
Kiniwa
Mamoru
M
Tsujimoto
Gozoh
G
Kohri
Kenjiro
K
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D009281:Naphthalenes; D010879:Piperazines; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; C064357:naftopidil