Prostate cancer continues to afflict many thousands of American males and is the cause of approximately 30000 deaths per year (Greenlee et al, 2000). Although therapeutic modalities such as androgen ablation and radical prostatectomy are considered curative for localised disease, no treatment for metastatic prostate cancer is available, which shows a significant increase in length of life (Raghavan, 1988; Crawford et al, 1989; Catalona et al, 1993). The therapeutic significance of apoptosis in the treatment of prostate cancer emerges from evidence suggesting that like normal prostate epithelial cells, prostate cancer cells maintain sensitivity to androgens and undergo apoptosis in response to androgen withdrawal (Isaacs, 1994; Boyle, 2000). Androgen-independent prostate cancer cells still contain the apoptotic machinery and can undergo apoptosis in response to hormone-independent approaches (Bruckheimer and Kyprianou, 2000). Reactivation of cell death pathways in prostate cancer cells represents a powerful approach for pharmacological intervention, and consequently targeting the apoptotic signalling in prostate cells has been the focus of numerous investigations (Bruckheimer and Kyprianou, 2000).
A class of pharmacological agents, the α1-adrenoceptor antagonists, originally used as antihypertensive agents (Young and Brogden, 1988), have been safely used as standard medical therapy for benign prostatic hyperplasia (BPH) and the long-term relief of lower urinary tract symptoms (LUTS) (Caine, 1988; Kirby, 1996). Growing evidence suggests that two of these clinically used α1-adrenoceptor antagonists, doxazosin and terazosin, that share a similar chemical structure, the quinazoline nucleus (Figure 1), exert a potent apoptotic effect against prostate cancer cells (Kyprianou and Benning, 2000), via an α1-adrenoceptor-independent mechanism (Benning and Kyprianou, 2002) and suppression of tumour vascularity (Keledjian et al, 2001).
Apoptosis induction by androgen withdrawal in normal and hormone-dependent malignant prostate involves the transforming growth factor-β1 (TGF-β1) signalling pathway (Kyprianou and Isaacs, 1989). Recent immunohistochemical analysis of BPH tissue revealed an increase in TGF-β1 expression but no change in TGF-βII receptor (TβRII) in patients who had undergone treatment with the clinically used quinazoline-based α1-adrenoceptor antagonist terazosin (Glassman et al, 2001). The TGF-β1 signalling system normally functions to inhibit proliferation and induce apoptosis of epithelial and endothelial cells (Massague et al, 2000); its signal transduction pathway involves the receptor-mediated activation by phosphorylation of the intracellular effectors, Smad2, Smad3 and Smad4, and their translocation to the nucleus where they regulate gene transcription (Massague, 2000). Expression and activation of these intracellular effectors of the TGF-β1 pathway are critical to the execution of the apoptotic process (DeCaestecker et al, 2000). An inhibitory regulator of TGF-β1 signalling, Smad7, (Whitman, 1997) is regulated by TGF-β1 specifically via Smad3 and Smad4 indicating a negative feedback mechanism (Hayashi et al, 1997). Smad7 is induced during apoptosis of prostate epithelial cells (Brodin et al, 1999) and has recently been shown to sensitise other cell types to apoptosis (Mazars et al, 2001; Schiffer et al, 2001).
The TGF-β1-inducible early gene (TIEG1) is another factor that induces apoptosis in breast, lung and kidney cells (Tachibana et al, 1997; Chalaux et al, 1999; Hefferan et al, 2000), potentially by downregulating the antiapoptotic protein bcl-2 (Chalaux et al, 1999).
This study aimed to identify the molecular mechanism underlying the apoptotic action of quinazoline-based α1-adrenoceptor antagonists against prostate cancer cells. Our findings demonstrate that doxazosin induces the apoptotic signalling potentially via the activation of TGF-β1 pathway with a potential involvement of NF-κB nuclear effectors.