Alpha adrenergic receptors in renal pelvis and calyces: can rat models be used?

Karabacakb, Osman Raif; Şener, Nevzat Can; Yılmazer, Demet; Karabacak, Yurdum; Göktuğ, Hasan Nedim Göksel; Yigitbasi, Orhan; Alper, Murat

doi:10.1590/s1677-5538.ibju.2014.05.14

Cited by 4 publications

(4 citation statements)

References 29 publications

(33 reference statements)

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“…More recently the potential efficacy of these drugs in the treatment of prostate cancer has been proposed, due to the ability to induce apoptosis and overcome anoikis resistance in tumor cells [14][15][16][17][18]. Reassuringly, in earlier clinical trials assessing their use for the treatment of BPH, they were well tolerated with only reversible adverse effects in a minority of patients, including postural hypotension (4%), asthenia or light-headedness (10%), somnolence (3%) and retrograde ejaculation (8%) [19,20].…”

mentioning

confidence: 99%

Repurposing of α1-Adrenoceptor Antagonists: Impact in Renal Cancer

Mihalopoulos

Dovey

Archer

et al. 2020

Cancers

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Renal cancer ranks twelfth in incidence among cancers worldwide. Despite improving outcomes due to better therapeutic options and strategies, prognosis for those with metastatic disease remains poor. Current systemic therapeutic approaches include inhibiting pathways of angiogenesis, immune checkpoint blockade, and mTOR inhibition, but inevitably resistance develops for those with metastatic disease, and novel treatment strategies are urgently needed. Emerging molecular and epidemiological evidence suggests that quinazoline-based α1-adrenoceptor-antagonists may have both chemopreventive and direct therapeutic actions in the treatment of urological cancers, including renal cancer. In human renal cancer cell models, quinazoline-based α1-adrenoceptor antagonists were shown to significantly reduce the invasion and metastatic potential of renal tumors by targeting focal adhesion survival signaling to induce anoikis. Mechanistically these drugs overcome anoikis resistance in tumor cells by targeting cell survival regulators AKT and FAK, disrupting integrin adhesion (α5β1 and α2β1) and engaging extracellular matrix (ECM)-associated tumor suppressors. In this review, we discuss the current evidence for the use of quinazoline-based α1-adrenoceptor antagonists as novel therapies for renal cell carcinoma (RCC) and highlight their potential therapeutic action through overcoming anoikis resistance of tumor epithelial and endothelial cells in metastatic RCC. These findings provide a platform for future studies that will retrospectively and prospectively test repurposing of quinazoline-based α1-adrenoceptor-antagonists for the treatment of advanced RCC and the prevention of metastasis in neoadjuvant, adjuvant, salvage and metastatic settings.

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confidence: 99%

Repurposing of α1-Adrenoceptor Antagonists: Impact in Renal Cancer

Mihalopoulos

Dovey

Archer

et al. 2020

Cancers

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“…These subtypes can be pharmacologically distinguished by their differential binding to alpha-1 blockers and may be linked to distinct second-messenger systems [37]. In the kidney, α1A-and α1D-ARs are the major functional subtypes other than α1B [38]. A previous in vitro study on rat cell lines transfected with human α1-AR cDNAs demonstrated that α1A-and α1D-ARs mediate G 1 -S cell cycle arrest, whereas the α1B-ARs mediate cell cycle progression [39].…”

Section: Discussion/conclusionmentioning

confidence: 99%

Alpha-1 blocker use increased risk of subsequent renal cell carcinoma: A nationwide population-based study in Taiwan

Sung

Chen

et al. 2020

PLoS ONE

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Elevated Renal cell carcinoma (RCC) risk has been associated with the use of several antihypertensive medications but has not yet been elucidated in the populations prescribed alpha-1 blockers that are commonly used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS-BPH). The aim of the present study was to investigate the association between alpha-1 blocker use and the risk of developing RCC using a nationwide population-based database in Taiwan. Patients who were treated with alpha-1 blockers for at least 28 days were identified through the Taiwan National Health Insurance Research Database from 2000 to 2010. The unexposed participants were matched with the exposed cases according to age, sex, and index year at a ratio of 3:1. Cox proportional hazards regression, stratified by sex and comorbidities and adjusted for age, was performed to estimate hazard ratios (HRs) for the risk of subsequent RCC. Among 2,232,092 subjects, patients who received alpha-1 blocker treatment had a higher risk of RCC than the unexposed group. Taking into account hypertension and BPH, the adjusted HR was significantly higher in male alpha-1 blocker users who had no BPH and either the presence (HR: 1.63, 95% confidence interval [CI] = 1.22–2.18) or absence (HR: 2.31, 95% CI = 1.40–3.81) of hypertension than in men not receiving these drugs. Taken together, male alpha-1 blocker users who had no comorbidity of BPH exhibited an increased risk for developing RCC independent of hypertension. Further study is warranted to elucidate the underlying mechanisms of this association.

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“…2). Additional evidence demonstrated the expression of α1A in the cortex, pelvis, calyces, blood vessels and tubules of the kidney [15][16][17]. The α1Asubtype predominantly regulates smooth muscle tone in the urethra, prostate and bladder neck [18,19].…”

Section: Distribution Of Selective α-And β-Adrenergic Receptors (Adrenoceptors)mentioning

confidence: 99%

Role of α- and β-adrenergic signaling in phenotypic targeting: significance in benign and malignant urologic disease

et al. 2021

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The urinary tract is highly innervated by autonomic nerves which are essential in urinary tract development, the production of growth factors, and the control of homeostasis. These neural signals may become dysregulated in several genitourinary (GU) disease states, both benign and malignant. Accordingly, the autonomic nervous system is a therapeutic target for several genitourinary pathologies including cancer, voiding dysfunction, and obstructing nephrolithiasis. Adrenergic receptors (adrenoceptors) are G-Protein coupled-receptors that are distributed throughout the body. The major function of α1-adrenoceptors is signaling smooth muscle contractions through GPCR and intracellular calcium influx. Pharmacologic intervention of α-and β-adrenoceptors is routinely and successfully implemented in the treatment of benign urologic illnesses, through the use of α-adrenoceptor antagonists. Furthermore, cell-based evidence recently established the antitumor effect of α1-adrenoceptor antagonists in prostate, bladder and renal tumors by reducing neovascularity and impairing growth within the tumor microenvironment via regulation of the phenotypic epithelial-mesenchymal transition (EMT). There has been a significant focus on repurposing the routinely used, Food and Drug Administration-approved α1-adrenoceptor antagonists to inhibit GU tumor growth and angiogenesis in patients with advanced prostate, bladder, and renal cancer. In this review we discuss the current evidence on (a) the signaling events of the autonomic nervous system mediated by its cognate α- and β-adrenoceptors in regulating the phenotypic landscape (EMT) of genitourinary organs; and (b) the therapeutic significance of targeting this signaling pathway in benign and malignant urologic disease.

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Alpha adrenergic receptors in renal pelvis and calyces: can rat models be used?

Abstract: ARTICLE INFO________________________________________ We aimed, in

Cited by 4 publications

References 29 publications

Repurposing of α1-Adrenoceptor Antagonists: Impact in Renal Cancer

Repurposing of α1-Adrenoceptor Antagonists: Impact in Renal Cancer

Alpha-1 blocker use increased risk of subsequent renal cell carcinoma: A nationwide population-based study in Taiwan

Role of α- and β-adrenergic signaling in phenotypic targeting: significance in benign and malignant urologic disease

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Alpha adrenergic receptors in renal pelvis and calyces: can rat models be used?

Abstract: ARTICLE INFO______________________________________________________________ ______________________ We aimed, in

Cited by 4 publications

References 29 publications

Repurposing of α1-Adrenoceptor Antagonists: Impact in Renal Cancer

Repurposing of α1-Adrenoceptor Antagonists: Impact in Renal Cancer

Alpha-1 blocker use increased risk of subsequent renal cell carcinoma: A nationwide population-based study in Taiwan

Role of α- and β-adrenergic signaling in phenotypic targeting: significance in benign and malignant urologic disease

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Abstract: ARTICLE INFO________________________________________ We aimed, in