N. Kyprianou et Cm. Benning, Suppression of human prostate cancer cell growth by alpha 1-adrenoceptor antagonists doxazosin and terazosin via induction of apoptosis, CANCER RES, 60(16), 2000, pp. 4550-4555
Recent evidence from our laboratory has demonstrated that alpha 1-adrenocep
tor antagonists doxazosin and terazosin induced apoptosis in prostate epith
elial and smooth muscle cells in patients with benign prostatic hypertrophy
(BPH; J, Urol,, 159: 1810-1815, 1998; J, Urol,, 161: 2002-2007, 1999, In t
his study, we investigated the biological action of three alpha 1-adrenocep
tor antagonists, doxazosin, terazosin, and tamsulosin, against prostate can
ter cell growth. The antigrowth effect of the three alpha 1-adrenoceptor an
tagonists was examined in two human prostate cancer cell lines, PC-3 and DU
-145, and a prostate smooth muscle cell primary culture, SMC-1, on the basi
s of: (a) cell viability assay; (b) rate of DNA synthesis; and (c) inductio
n of apoptosis. Our results indicate that treatment of prostate cancer cell
s with doxazosin or terazosin results in a significant loss of cell viabili
ty, via induction of apoptosis in a dose-dependent manner, whereas tamsulos
in had no effect on prostate cell growth, Neither doxazosin nor terazosin e
xerted a significant effect on the rate of cell proliferation in prostate c
ancer cells. Exposure to phenoxy-benzamine, an irreversible inhibitor of al
pha 1-adrenaceptors, does not abrogate the apoptotic effect of doxazosin or
terazosin against human prostate cancer or smooth muscle cells. This sugge
sts that the apoptotic activity of doxazosin and terazosin against prostate
cells is independent of their capacity to antagonize al-adrenoceptors. Fur
thermore, an in vivo efficacy trial demonstrated that doxazosin administrat
ion (at tolerated pharmacologically relevant doses) in SCID mice bearing PC
-3 prostate cancer xenografts resulted in a significant inhibition of tumor
growth. These findings demonstrate the ability of doxazosin and terazosin
(but not tamsulosin) to suppress prostate cancer cell growth in vitro and i
n vivo by inducing apoptosis without affecting cell proliferation, This evi
dence provides the rationale for targeting both drugs, already in clinical
use and with established adverse-effect profiles, against prostatic tumors
for the treatment of advanced prostate cancer.