Previous studies documented the ability of quinazoline-based alpha1-adrenoceptor 
antagonists to induce apoptosis in prostate cancer cells via an alpha 
1-adrenoceptor-independent mechanism. In this study we investigated the 
molecular events initiating this apoptotic effect. Since transforming growth 
factor-beta 1 (TGF-beta 1) mediates prostate epithelial cell apoptosis, we 
hypothesised that the activation of the TGF-beta 1 pathway underlies the 
quinazoline-based apoptotic effect in prostate cancer cells. Treatment of the 
androgen-independent human prostate cancer cells PC-3 with doxazosin resulted in 
a strong caspase-3 activation within 24 h, whereas tamsulosin, a 
sulphonamide-based alpha 1-adrenoceptor antagonist, had no significant apoptotic 
effect against prostate cancer cells. To identify the molecular components 
involved in this quinazoline-mediated apoptosis, cDNA microarray analysis of 
PC-3 prostate cancer cells treated with doxazosin (3 h) was performed. Induced 
expression of several genes was observed including p21(WAF-1) and I kappa B 
alpha (inhibitor of NF-kappa B alpha). Relative quantitative reverse 
transcription-polymerase chain reaction analysis revealed induction of several 
TGF-beta1 signalling effectors: Induction of mRNA for Smad4 and the 
TGF-beta1-regulated apoptosis-inducing transcription factor TGF-beta1-inducible 
early gene (TIEG1) was detected within the first 6 h of doxazosin treatment. 
Upregulation of I kappa B alpha at both the mRNA and protein level was also 
detected after 6 h of treatment. Furthermore, doxazosin resulted in a 
considerable elevation in Smad4 and TIEG protein expression (6 h). A 'latent' 
increase in TGF-beta mRNA expression was detected after 48 h of treatment. These 
findings suggest that the quinazoline-based doxazosin mediates prostate cancer 
apoptosis by initially inducing the expression of TGF-beta1 signalling effectors 
and subsequently I kappa B alpha. The present study provides an initial insight 
into the molecular targets of the apoptotic action of quinazolines against 
prostate cancer cells.