Pharmacological Exploitation of the α1-Adrenoreceptor Antagonist Doxazosin to Develop a Novel Class of Antitumor Agents That Block Intracellular Protein Kinase B/Akt Activation

Shaw, Yeng-Jeng; Yang, Yating; Garrison, Jason B.; Kyprianou, Natasha; Chen, Ching‐Shih

doi:10.1021/jm049752k

Cited by 52 publications

(36 citation statements)

References 15 publications

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“…We recently reported that doxazosin-induced apoptosis in prostate cancer cells was mediated via inhibition of intracellular Akt activation by targeting its phosphorylation (18). Figure 6 shows a decrease in Akt phosphorylation with no apparent change in Akt protein levels in response to doxazosin (25 Amol/L) in PC-3 cells following normalization to actin.…”

Section: Resultsmentioning

confidence: 91%

Doxazosin Induces Apoptosis of Benign and Malignant Prostate Cells via a Death Receptor–Mediated Pathway

Garrison

Kyprianou

2006

Cancer Research

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Quinazoline-based A 1 -adrenoceptor antagonists such as doxazosin and terazosin have been previously shown to induce apoptosis in prostate cancer cells via an A 1 -adrenoceptorindependent pathway, involving activation of transforming growth factor-B1 (TGF-B1) signaling. In this study, the molecular events initiating this apoptotic effect were further investigated in vitro using the human androgen-independent prostate cancer cells PC-3 and the human benign prostate epithelial cells BPH-1. Quantitative microarray assays were done in PC-3 and BPH-1 cells after treatment with doxazosin (25 Mmol/L, 6 and 24 hours) to identify the early gene changes. Transient changes in the expression of several apoptosis regulators were identified, including up-regulation of Bax and Fas/CD95 and down-regulation of Bcl-xL and TRAMP/Apo3. Moreover, there were significant changes in the expression pattern of signaling components of the extracellular matrix such as integrins A 2 , A V , B 1 , and B 8 . Western blot analysis revealed activation of caspase-8 and caspase-3 within the first 6 to 12 hours of treatment with doxazosin in both PC-3 and BPH-1 cells. Doxazosin-induced apoptosis was blocked by specific caspase-8 inhibitors, supporting the functional involvement of caspase-8 in doxazosin-induced apoptosis. The effect of doxazosin on recruitment of Fas-associated death domain (FADD) and procaspase-8 to the Fas receptor was examined via analysis of death-inducing signaling complex formation. Doxazosin increased FADD recruitment and subsequent caspase-8 activation, implicating Fas-mediated apoptosis as the underlying mechanism of the effect of doxazosin in prostate cells. These results show that doxazosin exerts its apoptotic effects against benign and malignant prostate cells via a death receptor-mediated mechanism with a potential integrin contribution towards cell survival outcomes. (Cancer Res 2006; 66(1): 464-72)

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Section: Resultsmentioning

confidence: 91%

Doxazosin Induces Apoptosis of Benign and Malignant Prostate Cells via a Death Receptor–Mediated Pathway

Garrison

Kyprianou

2006

Cancer Research

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“…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). Doxazosin increased the apoptotic rate and total cell death rate of the HeLa cells in a dose-dependent manner and upregulated the expression of AP-2alpha and caspase-3 (Gan et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Possible Anticancer Activity of Rosuvastatine, Doxazosin, Repaglinide and Oxcarbazepin

Sharkawi¹,

Shemy²,

Khaled³

2014

Asian Pacific Journal of Cancer Prevention

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Drewa

Wolski

Misterek

et al. 2007

Prostate Cancer Prostatic Dis

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Doxazosin triggers apoptosis via an imprecisely defined receptor mechanism that is related to tumor necrosis factor receptors (TNFRs). The aim of this study was to determine CD95, TNFR-1, TNFR-2, CD40 expression in primary prostate epithelial cultures incubated with doxazosin. Epithelial cultures were cultivated from 10 benign prostate hyperplasia patients. The cells were incubated with 20, 50 and 80 lM of doxazosin. Apoptosis was confirmed by fluorescence microscopy and flow cytometry. The cells were analyzed for expression of FAS, CD40, TNFR-1 and TNFR-2 by flow cytometry. Early apoptotic cells were present in all groups. A positive correlation was noticed between doxazosin dose and TNFR-1-, -2-positive cells. A decrease of CD40-positive cell population was observed in the lowest concentration. A decrease of mean fluorescence intensity signal of CD40 and CD95 was observed in the lowest concentration. Doxazosin-triggered apoptosis was doseindependent. The initiation of apoptosis was a result of receptors 'crosstalk' rather than a single receptor pathway activation. TNF receptor self-assembly process should be checked as a potential mechanism leading to apoptosis after doxazosin treatment.

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Pharmacological Exploitation of the α1-Adrenoreceptor Antagonist Doxazosin to Develop a Novel Class of Antitumor Agents That Block Intracellular Protein Kinase B/Akt Activation

Cited by 52 publications

References 15 publications

Doxazosin Induces Apoptosis of Benign and Malignant Prostate Cells via a Death Receptor–Mediated Pathway

Doxazosin Induces Apoptosis of Benign and Malignant Prostate Cells via a Death Receptor–Mediated Pathway

Possible Anticancer Activity of Rosuvastatine, Doxazosin, Repaglinide and Oxcarbazepin

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

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