Anoikis induction by quinazoline based α1-adrenoceptor antagonists in prostate cancer cells: Antagonistic effect of BCL-2

Purpose: The ability of the quinazoline derived α1-adrenoceptor antagonists doxazosin and terazosin to induce apoptosis in benign and malignant prostate cells has been established. In this study we investigated the effect of the 2 piperazidinyl quinazoline based α1-adrenoceptor antagonists and the methoxybenzene sulfonamide α1-antagonist tamsulosin on human prostate cancer cell adhesion. Materials and Methods: Androgen independent PC-3 prostate cancer cells and PC-3 transfectant clones over expressing the apoptosis suppressor bcl-2 were used as an in vitro model. Cells were treated with pharmacologically relevant doses of I of the 3 α1-adrenoceptor antagonists and the effect on cell viability/cell adhesion on various substrates was examined. Analysis of expression of key attachment factors, such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor-α, was performed. Results: Our results indicate a significant decrease in prostate cancer cell adhesion to gelatin and collagen but not to fibronectin in prostate cancer cells treated with doxazosin or terazosin (25 μM.) compared with untreated control cultures (p <0.05). In contrast, tamsulosin had no effect on prostate cancer cell adhesion. The 2 quinazolines doxazosin and terazosin but not tamsulosin had a significant inhibitory effect on prostate tumor cell invasion. In bcl-2 over expressing prostate cancer cells there was significant suppression of doxazosin induced anoikis and cell invasion compared with neocontrol transfectants (p <0.05). Doxazosin resulted in transient down-regulation (2-fold decrease) of VEGF at the mRNA and protein levels, as detected by reverse transcriptase-polymerase chain reaction and Western blotting, respectively. No significant changes in the expression profile of hypoxia inducible factor-1α were observed after treatment with quinazolines. Furthermore, bcl-2 resulted in partial reversion of the doxazosin induced VEGF decrease. Conclusions: These findings demonstrate that the quinazoline derived α1-antagonists doxazosin and terazosin but not sulfonamide based tamsulosin induce anoikis and inhibit prostate cancer cell invasion, an effect that is antagonized by bcl-2. This molecular basis of an α1-adrenoceptor independent action against prostate cancer cells by the quinazolines may have potential therapeutic significance in prostate cancer.