Pharmacological exploitation of the α1-adrenoreceptor antagonist doxazosin to develop a novel class of antitumor agents that block intracellular protein kinase B/Akt activation

Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio, United States
Journal of Medicinal Chemistry (Impact Factor: 5.48). 09/2004; 47(18):4453-62. DOI: 10.1021/jm049752k
Source: PubMed

ABSTRACT The alpha1-adrenoreceptor antagonist doxazosin induces apoptosis in malignant cells with moderate potency via an alpha1-adrenoreceptor-independent mechanism. Here, we demonstrate that the ability of doxazosin to induce apoptosis in PC-3 prostate cancer cells was, in part, attributable to the inhibition of protein kinase B (PKB)/Akt activation. The separation of the effect of doxazosin on apoptosis from its original pharmacological activity provides molecular underpinnings to develop novel antitumor agents. Replacement of the (2,3-dihydro-benzo[1,4]dioxane)-carbonyl moiety of doxazosin with aryl-sulfonyl functions dramatically improves the potency in facilitating Akt deactivation and inducing apoptosis. The optimal compounds, 33 and 44, were effective in apoptosis induction at low micromolar concentrations irrespective of androgen dependency and p53 functional status. Both agents were active in suppressing the growth of a panel of 60 cancer-cell lines with IC50 values of 2.2 and 1.5 microM, respectively. Together, these in vitro efficacy data suggest the translational potential of these agents in prostate cancer treatment.

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Available from: Arthur Y. Shaw, Jul 23, 2015
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    • "In turn, restoring or facilitating anoikis and inhibiting angiogenesis are two targets of anticancer therapy. Quinazoline-based drugs terazosin and doxazosin have been shown to facilitate anoikis in prostate cells by death receptormediated mechanisms involving death-inducing signaling complex formation/caspase-8 activation and inhibition of Akt survival signaling, consequential to the disruption of cell attachment to the extracellular matrix via targeting integrins (Shaw et al. 2004; Garrison and Kyprianou 2006; Garrison et al. 2007). These mechanisms are intimately connected with the ability of terazosin and doxazosin to induce TGF-β1- mediated apoptosis independent of α 1 -adrenoceptor action (Partin et al. 2003). "
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    ABSTRACT: Doxazosin and related, quinazoline-based alpha(1)-adrenoceptor antagonists can induce apoptosis in prostate and various other normal, benign, smooth muscle, endothelial and malignant cells. Such apoptosis-inducing effects occur independently of alpha(1)-adrenoceptor antagonism and typically require much high concentrations than those required for receptor occupancy. Several studies have invested efforts towards the elucidation of the molecular mechanisms underlying doxazosin-induced apoptosis. These include various tumor cells, cardiomyocytes, endothelial cells and bladder smooth muscle cells. While the high concentrations of doxazosin required to induce apoptosis challenge the use of this and related drugs for clinical optimization of apoptosis induction, such quinazoline structure may represent chemical starting points to develop more potent apoptosis-inducing agents free of alpha(1)-adrenoceptor antagonistic action and suitable for cancer treatment with minimal and well-tolerated side effects.
    Archiv für Experimentelle Pathologie und Pharmakologie 11/2009; 380(6):473-7. DOI:10.1007/s00210-009-0462-4 · 2.36 Impact Factor
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    • "Apoptosis induction proceeds via two classic pathways, the extrinsic death-receptor pathway involving caspase 8 activation, and the intrinsic pathway involving mitochondrial cytochrome C and caspase 9 activation (Wolf and Green, 1999). We recently demonstrated that doxazosin (quinazoline-α1-adrenoceptor antagonist) activates the receptor-mediated pathway of apoptosis via Fas-associated death domain (FADD) and caspase-8 activation (Garrison and Kyprianou, 2006) in both prostate epithelial and endothelial cells by promoting TGF-β1 signaling via IκB induction (Garrison and Kyprianou, 2004), and by inhibiting protein kinase B/Akt activation to promote anoikis (Grossmann, 2002; Keledjian and Kyprianou, 2002; Shaw et al, 2004). The quinazolines suppress angiogenesis by targeting vascular endothelial growth factor (VEGF)-mediated endothelial tube formation (Panet al, 2003; Keledjian et al, 2005). "
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    ABSTRACT: Previous studies documented that human bladder cancer cells are sensitive to the apoptotic effects of quinazoline-derived α1-adrenoreceptor antagonists and bladder tumors exhibit reduced tissue vascularity in response to terazosin. More recent evidence suggests that exposure to quinazoline α1-adrenorecptor antagonists leads to a significant reduction in prostate cancer incidence. This retrospective observational cohort study was conducted to determine whether male patients treated with quinazoline α1-adrenoceptor antagonists for either benign prostate hyperplasia (BPH) or hypertension have a decreased risk of developing bladder cancer. Review of the medical records of all male patients enrolled at the Lexington Veterans Administration (VA) Medical Center identified men exposed to quinazoline-based α1-adrenoceptor antagonists (Jan 1, 1998-Dec 31, 2002) for either hypertension and/or benign prostate obstructive symptoms. The whole group of 27,138 male patients was linked to the Markey Cancer Center's Kentucky Cancer Registry (KCR), part of the NCI's Surveillance, Epidemiology, and End Results (SEER) Program, to identify all incident bladder cancer cases diagnosed in this population. Measures of disease incidence, relative risk, and attributable risk were calculated to compare the risk of developing bladder cancer for α1-blocker-exposed versus unexposed men. A two-by-two contingency table of α1-antagonist exposure versus bladder cancer diagnoses was constructed and the relative risk was calculated. Our analysis revealed a cumulative bladder cancer incidence of 0.24% among the α1-blocker-exposed men compared to 0.42% in the unexposed group. Thus, there was a risk difference of -0.0018, which indicates that 1.8 fewer bladder cancer cases developed per 1000 exposed men. Alternatively stated, 556 men would need to be treated with quinazoline α1-blockers to prevent one case of bladder cancer. Exposure to quinazoline α1-blockers thus may have prevented 7 to 8 bladder cancer cases among the 4173 treated men during the study period. The data yield an unadjusted risk ratio of 0.57 (95% CI: 0.30, 1.08) and therefore, men treated with α1-adrenoreceptor antagonists have a 43% lower relative risk of developing bladder cancer than unexposed men (p=0.083). Our inability to determine person-years at risk of developing bladder cancer for each unexposed control patient, was a limitation for calculating an incidence ratio and rate difference. These results offer an initial indication that exposure to doxazosin and terazosin decreases the incidence of bladder cancer. This is the first epidemiological evidence that the anti-tumor action of quinazoline-based α1-antagonists may potentially translate into a protective effect from bladder cancer development.
    Gene therapy & molecular biology 01/2008; 12(2):253-258. · 0.43 Impact Factor
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    • "RESEARCH ARTICLE and cell apoptosis, namely, 1) activation of transforming growth factor-b and InB pathways [14]; 2) inhibition of protein kinase B/Akt activation [15]; 3) induction of death receptor – mediated apoptosis [16]; 4) increase in Bax expression [17]; and 5) reduction in focal adhesion kinase [18]. There is another implication behind the discovery of doxazosin in anticancer study—''old drugs with new indication .'' "
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    ABSTRACT: Quinazoline-based alpha1-adrenoceptor antagonists, in particular doxazosin and terazosin, are suggested to display antineoplastic activity against prostate cancers. However, there are few studies elucidating the effect of prazosin. In this study, prazosin displayed antiproliferative activity superior to that of other alpha1-blockers, including doxazosin, terazosin, tamsulosin, and phentolamine. Prazosin induced G2 checkpoint arrest and subsequent apoptosis in prostate cancer PC-3, DU-145, and LNCaP cells. In p53-null PC-3 cells, prazosin induced an increase in DNA strand breaks and ATM/ATR checkpoint pathways, leading to the activation of downstream signaling cascades, including Cdc25c phosphorylation at Ser216, nuclear export of Cdc25c, and cyclin-dependent kinase (Cdk) 1 phosphorylation at Tyr15. The data, together with sustained elevated cyclin A levels (other than cyclin B1 levels), suggested that Cdk1 activity was inactivated by prazosin. Moreover, prazosin triggered mitochondria-mediated and caspase-executed apoptotic pathways in PC-3 cells. The oral administration of prazosin significantly reduced tumor mass in PC-3-derived cancer xenografts in nude mice. In summary, we suggest that prazosin is a potential antitumor agent that induces cell apoptosis through the induction of DNA damage stress, leading to Cdk1 inactivation and G2 checkpoint arrest. Subsequently, mitochondria-mediated caspase cascades are triggered to induce apoptosis in PC-3 cells.
    Neoplasia (New York, N.Y.) 11/2007; 9(10):830-9. DOI:10.1593/neo.07475 · 5.40 Impact Factor
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