Recent evidence suggests that the
quinazoline-based alpha1-adrenoceptor antagonists,
doxazosin and
terazosin, exhibit a potent apoptotic effect against prostate
tumor epithelial cells, whereas
tamsulosin, a
sulfonamide-based alpha1-adrenoceptor antagonist, was ineffective in inducing a similar apoptotic effect against prostate cells (
Cancer Res., 60: 4550-4555, 2000). In this study, to identify the precise molecular mechanism underlying this apoptosis induction, we examined whether
doxazosin and
terazosin (both piperazinyl
quinazolines) affect prostate growth via an alpha1-adrenoceptor-independent action. Transfection-mediated overexpression of alpha1-adrenoceptor in human
prostate cancer cells, DU-145 (that lack alpha1-
adrenoceptor), did not alter the ability of
prostate cancer cells to undergo apoptosis in response to
quinazolines. Significantly enough, there was no modification of the apoptotic threshold of the
androgen-sensitive
prostate cancer cells, LNCaP, to either
quinazoline-based alpha1-agonist by
androgens. Furthermore, human normal prostate epithelial cells exhibited a very low sensitivity to the apoptotic effects of
doxazosin compared with that observed for the malignant prostate cells. These findings provide the first evidence that the apoptotic activity of the
quinazoline-based alpha1-adrenoceptor antagonists (
doxazosin and
terazosin) against
prostate cancer cells is independent of: (a) their capacity to antagonize alpha1-
adrenoceptors; and (b) the
hormone sensitivity status of the cells. This may have potential therapeutic significance in the use of
quinazoline-based alpha1-adrenoceptor antagonists (already in clinical use for the treatment of
hypertension and benign prostate
hyperplasia) for the treatment of
androgen-independent human
prostate cancer.