Anti‐angiogenic effects and mechanism of prazosin

Cui, Liao; Guh, Jih‐Hwa; Chueh, Shih-Chieh; Yu, Hong‐Jeng

doi:10.1002/pros.21313

Cited by 29 publications

(20 citation statements)

References 22 publications

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“…A variety of the mechanisms for antitumor actions of α 1 -adrenoceptor blockers have been proposed: mitochondria-mediated activation of caspase-3/-9 and cjun N-terminal kinase 1/2, recruitment of Fas-associated death domain and the ensuing activation of caspase-8, activation of transforming growth factor-β 1 signaling pathway and IκBα induction, or an antagonistic effect of Bcl-2. α 1 -Adrenoceptor blockers, alternatively, exhibit antiangiogenic effects, thereby suppressing cell growth in human prostate cancer [25][26][27][28] or human bladder cancer [29]. α 1 -Adrenoceptor blockers also modulate differentiation and cell death of human erythroleukemia cells by a mechanism independent of α 1 -adrenergic blocking [30].…”

Section: Resultsmentioning

confidence: 99%

Antitumor Action of a₁-Adrenoceptor Blockers on Human Bladder, Prostate and Renal Cancer Cells

Gotoh

Nagaya²,

Kanno³

et al. 2012

Pharmacology

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The present study investigated the antitumor action of α₁-adrenoceptor blockers on human bladder, prostate and renal cancer cells. For bladder cancer cell lines used here such as 253J, 5637, KK-47, T24 and UM-UC-3 cells, prazosin, a selective α₁-adrenoceptor blocker, reduced cell viability at concentrations more than 30 µmol/l. Likewise, naftopidil, a blocker of α_1A- and α_1D-adrenoceptors, reduced cell viability for all the bladder cancer cells used here in a concentration (10–100 µmol/l)-dependent manner, with a much greater advantage than prazosin. Naftopidil also reduced cell viability for human prostate cancer cell lines such as DU145, LNCap and PC-3 cells and ACHN human renal cancer cells, with a much higher potential than prazosin. Thus, the results of the present study suggest that naftopidil could be a beneficial antitumor drug for the treatment of urological cancers.

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Section: Resultsmentioning

confidence: 99%

Antitumor Action of a₁-Adrenoceptor Blockers on Human Bladder, Prostate and Renal Cancer Cells

Gotoh

Nagaya²,

Kanno³

et al. 2012

Pharmacology

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“…Blockade of ␣ 1 -ADR with prazosin or doxazosin in other cell types also introduced apoptosis (28,39). Previous reports also suggest that ␣ 1 -ADR survival signaling could be mediated by a mechanism downstream of ERK1/2, including the phosphorylation and inactivation of the Bad (54).…”

Section: Discussionmentioning

confidence: 93%

“…Repeated stress also increased transcripts for all ADRs expressed in Leydig cells (52), and catecholamines stimulated androgen production in rat (2), golden hamster (44), and Siberian hamster (43) cells. Because it is well known that ADRs play an important antiapoptotic role in breast cancer cells (28), human umbilical vascular endothelial cells (39), and cardiac myocytes (54), we speculated that this signaling pathway may also contribute to the control of apoptotic and/or antiapoptotic signaling and androgenesis in stressed animals.…”

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confidence: 99%

The opposite roles of glucocorticoid and α₁-adrenergic receptors in stress triggered apoptosis of rat Leydig cells

Andrić

Kojić

Bjelic

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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The stress-induced initiation of proapoptotic signaling in Leydig cells is relatively well defined, but the duration of this signaling and the mechanism(s) involved in opposing the stress responses have not been addressed. In this study, immobilization stress (IMO) was applied for 2 h daily, and animals were euthanized immediately after the first (IMO1), second (IMO2), and 10th (IMO10) sessions. In IMO1 and IMO2 rats, serum corticosterone and adrenaline were elevated, whereas serum androgens and mRNA transcription of insulin-like factor-3 in Leydig cells were inhibited. Reduced oxygen consumption and the mitochondrial membrane potential coupled with a leak of cytochrome c from mitochondria and increased caspase-9 expression, caspase-3 activity, and number of apoptotic Leydig cells was also observed. Corticosterone and adrenaline were also elevated in IMO10 rats but were accompanied with a partial recovery of androgen secretion and normalization of insulin-like factor-3 transcription coupled with increased cytochrome c expression, abolition of proapoptotic signaling, and normalization of the apoptotic events. Blockade of intratesticular glucocorticoid receptors diminished proapoptotic effects without affecting antiapoptotic effects, whereas blockade of intratesticular ␣1-adrenergic receptors diminished the antiapoptotic effects without affecting proapoptotic effects. These results confirmed a critical role of glucocorticoids in mitochondria-dependent apoptosis and showed for the first time the relevance of stress-induced upregulation of ␣ 1-adrenergic receptor expression in cell apoptotic resistance to repetitive IMOs. The opposite role of two hormones in control of the apoptotic rate in Leydig cells also provides a rationale for a partial recovery of androgen production in chronically stressed animals. Leydig cells; immobilization stress; corticosterone; adrenaline; testis; apoptosis THE LEVELS OF TESTOSTERONE (T) in circulation reflect the steroidogenic capacity of individual testicular Leydig cells and the total number of these cells per testes (2,3,10,16). Because Leydig cells from adult animals are fully differentiated and rarely proliferate or die under normal physiological conditions, their steroidogenic capacity is controlled predominantly by the status of the hypothalamo-pituitary-gonadal axis via GnRH-LH secretory pathway (10, 23). The sustained stress lowers circulating LH and androgen levels (13,40,42), and acute stress also lowers T levels without changing circulating LH levels (35, 42). Furthermore, the reciprocal changes in plasma corticosterone (CORT) and T in stressed rats (45) and increase in steroidogenic capacity of Leydig cells induced by suppression of CORT levels (19) suggested that this stress hormone directly inhibits T biosynthesis.Several hypotheses have also been introduced to explain the mechanism by which glucocorticoids directly inhibit androgenesis. The CORT-induced decline in steroidogenic capacity could reflect inhibition of the expression (48) and activity (47) of T-biosynthetic...

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“…7) In addition, prazosin administration results in increased lipoprotein lipase (LPL) activity [8][9][10] and decreased 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity in serum. 11) We recently found that prazosin stimulated the release of hepatic triacylglyceride lipase (HTGL; EC 3.1.1.3) from primary cultured rat hepatocytes via the activation of phospholipase C (PLC).…”

mentioning

confidence: 99%

Adenosine 3′,5′-Cyclic Monophosphate Involvement in Hepatic Triacylglyceride Lipase Release from Prazosin-Stimulated Primary Cultured Rat Hepatocytes

Nakamura

Morita

2014

Biological & Pharmaceutical Bulletin

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We recently found that hepatic triglyceride lipase (HTGL) was released from primary cultured rat hepatocytes after treatment with prazosin, an antagonist of alpha-1 adrenoceptors. However, the details of prazosin-induced HTGL release remain uncertain. Here we investigated whether changes in cAMP levels in hepatocytes were related to HTGL release from prazosin-stimulated hepatocytes. When hepatocytes were treated with prazosin, cAMP levels during stimulated release of HTGL increased in a time-and dosedependent manner. Stimulated release of HTGL was suppressed by the adenylate cyclase inhibitors MDL-12,330A and 2′,5′-dideoxyadenosine. Further, cAMP-dependent protein kinase A (PKA) activity in prazosinstimulated hepatocytes also increased in a time-and dose-dependent manner. Moreover, prazosin-stimulated HTGL release was suppressed by the PKA inhibitors H-89 and KT5720. These results suggest that prazosinstimulated HTGL release from hepatocytes was due to cAMP production and partly due to subsequent PKA activation in hepatocytes.Key words prazosin; hepatic lipase; cAMP; protein kinase A; hepatocyteis a well-known antagonist of alpha-1 adrenoceptors, and it is used in pharmacotherapy for hypertension, prostatomegaly, 1,2) and pheochromocytoma. Its pharmacological effects result from inhibition of alpha-1 adrenoceptors of vascular smooth muscles and the sphincter muscle of the urethra.3,4) Prazosin also has other effects, including increasing high density lipoprotein (HDL) cholesterol levels in hypertensive patients after long-term administration, 5) improving posttraumatic stress disorder (PTSD) symptoms, 6) and inducing prostate cancer cell apoptosis.7) In addition, prazosin administration results in increased lipoprotein lipase (LPL) activity [8][9][10] and decreased 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity in serum. 11)We recently found that prazosin stimulated the release of hepatic triacylglyceride lipase (HTGL; EC 3.1.1.3) from primary cultured rat hepatocytes via the activation of phospholipase C (PLC).12) In this previous study, the region downstream to PLC was suggested to be highly involved in the Ca 2+ / calmodulin-dependent protein kinase-II rather than protein kinase C. However, other interactions may also have been involved.HTGL hydrolyzes triacylglycerides (TG) in HDL and intermediate density lipoproteins, and it is considered to play an important role in lipid metabolism. [13][14][15][16] However, effects of HTGL other than this remain to be investigated.HTGL is synthesized and secreted when it is partially glycosylated in hepatocytes.17) It is also anchored to the plasma membranes of endothelial cells by electrostatic binding with heparan sulfate proteoglycans.18) However, details regarding the regulation of HTGL release from hepatocytes remain uncertain.Thus, in this study, we investigated whether prazosinstimulated HTGL release from hepatocytes was due to a mechanism involving increased cAMP levels and a subsequent increase in protein kinase A (PKA) activity. MATERIALS AND METHOD...

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Anti‐angiogenic effects and mechanism of prazosin

Abstract: These data suggest that prazosin exhibits anti-angiogenic activity and differentially modulates apoptotic pathways depending on the cell type.

Cited by 29 publications

References 22 publications

Antitumor Action of a₁-Adrenoceptor Blockers on Human Bladder, Prostate and Renal Cancer Cells

Antitumor Action of a₁-Adrenoceptor Blockers on Human Bladder, Prostate and Renal Cancer Cells

The opposite roles of glucocorticoid and α₁-adrenergic receptors in stress triggered apoptosis of rat Leydig cells

Adenosine 3′,5′-Cyclic Monophosphate Involvement in Hepatic Triacylglyceride Lipase Release from Prazosin-Stimulated Primary Cultured Rat Hepatocytes

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Anti‐angiogenic effects and mechanism of prazosin

Abstract: These data suggest that prazosin exhibits anti-angiogenic activity and differentially modulates apoptotic pathways depending on the cell type.

Cited by 29 publications

References 22 publications

Antitumor Action of a1-Adrenoceptor Blockers on Human Bladder, Prostate and Renal Cancer Cells

Antitumor Action of a1-Adrenoceptor Blockers on Human Bladder, Prostate and Renal Cancer Cells

The opposite roles of glucocorticoid and α1-adrenergic receptors in stress triggered apoptosis of rat Leydig cells

Adenosine 3′,5′-Cyclic Monophosphate Involvement in Hepatic Triacylglyceride Lipase Release from Prazosin-Stimulated Primary Cultured Rat Hepatocytes

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Antitumor Action of a₁-Adrenoceptor Blockers on Human Bladder, Prostate and Renal Cancer Cells

Antitumor Action of a₁-Adrenoceptor Blockers on Human Bladder, Prostate and Renal Cancer Cells

The opposite roles of glucocorticoid and α₁-adrenergic receptors in stress triggered apoptosis of rat Leydig cells