Quinazoline-based α1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-β signalling and IκBα induction

Abstract

Previous studies documented the ability of quinazoline-based a1-adrenoceptor antagonists to induce apoptosis in prostate cancer cells via an a1-adrenoceptor-independent mechanism. In this study we investigated the molecular events initiating this apoptotic effect. Since transforming growth factor-b1 (TGF-b1) mediates prostate epithelial cell apoptosis, we hypothesised that the activation of the TGF-b1 pathway underlies the quinazoline-based apoptotic effect in prostate cancer cells. Treatment of the androgenindependent human prostate cancer cells PC-3 with doxazosin resulted in a strong caspase-3 activation within 24 h, whereas tamsulosin, a sulphonamide-based a1-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 IkBa (inhibitor of NF-kB alpha). Relative quantitative reverse transcription -polymerase chain reaction analysis revealed induction of several TGF-b1 signalling effectors: Induction of mRNA for Smad4 and the TGF-b1-regulated apoptosis-inducing transcription factor TGF-b1-inducible early gene (TIEG1) was detected within the first 6 h of doxazosin treatment. Upregulation of IkBa 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-b 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-b1 signalling effectors and subsequently IkBa. The present study provides an initial insight into the molecular targets of the apoptotic action of quinazolines against prostate cancer cells.

Possible Anticancer Activity of Rosuvastatine, Doxazosin, Repaglinide and Oxcarbazepin

“…Several signaling pathways have been identified to explain doxazosin-induced anoikis and cell apoptosis, namely through activation of transforming growth factor-b and InB pathways (Partin et al, 2003). inhibition of protein kinase B/Akt activation (Shaw et al, 2004); induction of death receptor-mediated apoptosis (Garrison and Kyprianou, 2006); increase in Bax expression (Chiang et al, 2005) and reduction in focal adhesion kinase (Walden et al, 2004).…”

The influence of α1-antagonist on the expression pattern of TNF receptor family in primary culture of prostate epithelial cells from BPH patients

“…Garrison and Kyprianou 9 have shown that doxazosin increased FADD recruitment and subsequent caspase-8 activation, implicating FAS-mediated apoptosis as a mechanism leading to apoptosis in prostate cells. Partin et al 7 have demonstrated that doxazosin treatment resulted in caspase-3 activation within 24 h. Caspase-3 is a crucial enzyme for the executive phase of apoptosis that can be activated after the stimulation of tumor necrosis factor family receptors. Konig et al 26,27 have demonstrated that TNF-a can be one of the key factors in the benign prostate hyperplasia (BPH) pathogenesis.…”

“…Many pathways leading to apoptosis within prostate have been proposed. [1][2][3][4][5][6][7][8] The recent results show that doxazosin triggers apoptosis within benign and malignant prostate cells via an imprecisely defined receptor mechanism related to tumor necrosis factor receptors family (TNFRs). [8][9][10][11][12] TNFRs such as CD95 (FAS), TNFR-1, TNFR-2 and CD40 may be responsible for triggering apoptosis.…”

Maspin sensitizes prostate cancer cells to doxazosin-induced apoptosis

“…We recently reported that the key identified molecular players of doxazosin action were members of the TGFb pathway such as Smad4 and TGFb1-inducible early gene (TIEG1) (Partin et al, 2003). In particular, increased expression of Smad4 was reported at the protein level 6 h after doxazosin treatment.…”

“…Recently, the quinazoline-based antagonists have been shown to exert potent apoptotic action against benign and malignant prostate cells mediated via transforming growth factor b (TGFb) signaling and activation of NF-kb pathway (Kyprianou and Benning, 2000;Benning and Kyprianou, 2002;Partin et al, 2003). In in vivo experimental models of both prostate cancer and BPH xenografts, doxazosin-induced apoptosis led to suppression of prostate growth without affecting their proliferative ability (Yang et al, 1997;Kyprianou and Benning, 2000).…”