|
1
|
Hassan M, Flanagan TW, Eshaq AM, Altamimi OK, Altalag H, Alsharif M, Alshammari N, Alkhalidi T, Boulifa A, El Jamal SM, Haikel Y, Megahed M. Reduction of Prostate Cancer Risk: Role of Frequent Ejaculation-Associated Mechanisms. Cancers (Basel) 2025; 17:843. [PMID: 40075690 PMCID: PMC11898507 DOI: 10.3390/cancers17050843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 02/21/2025] [Accepted: 02/26/2025] [Indexed: 03/14/2025] Open
Abstract
Prostate cancer (PCa) accounts for roughly 15% of diagnosed cancers among men, with disease incidence increasing worldwide. Age, family history and ethnicity, diet, physical activity, and chemoprevention all play a role in reducing PCa risk. The prostate is an exocrine gland that is characterized by its multi-functionality, being involved in reproductive aspects such as male ejaculation and orgasmic ecstasy, as well as playing key roles in the regulation of local and systemic concentrations of 5α-dihydrotestosterone. The increase in androgen receptors at the ventral prostate is the first elevated response induced by copulation. The regulation of prostate growth and function is mediated by an androgen-dependent mechanism. Binding 5-DHT to androgen receptors (AR) results in the formation of a 5α-DHT:AR complex. The interaction of the 5α-DHT:AR complex with the specific DNA enhancer element of androgen-regulated genes leads to the regulation of androgen-specific target genes to maintain prostate homeostasis. Consequently, ejaculation may play a significant role in the reduction of PCa risk. Thus, frequent ejaculation in the absence of risky sexual behavior is a possible approach for the prevention of PCa. In this review, we provide an insight into possible mechanisms regulating the impact of frequent ejaculation on reducing PCa risk.
Collapse
Affiliation(s)
- Mohamed Hassan
- Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France;
- Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France
- Research Laboratory of Surgery-Oncology, Department of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA;
| | - Thomas W. Flanagan
- Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, LA 70112, USA;
| | - Abdulaziz M. Eshaq
- Research Laboratory of Surgery-Oncology, Department of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA;
- Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, George Washington University, Washington, DC 20052, USA
| | - Osama K. Altamimi
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (O.K.A.); (H.A.); (M.A.); (N.A.); (T.A.)
| | - Hassan Altalag
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (O.K.A.); (H.A.); (M.A.); (N.A.); (T.A.)
| | - Mohamed Alsharif
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (O.K.A.); (H.A.); (M.A.); (N.A.); (T.A.)
| | - Nouf Alshammari
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (O.K.A.); (H.A.); (M.A.); (N.A.); (T.A.)
| | - Tamadhir Alkhalidi
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (O.K.A.); (H.A.); (M.A.); (N.A.); (T.A.)
| | - Abdelhadi Boulifa
- Berlin Institute of Health, Charité University Hospital, 10117 Berlin, Germany;
- Competence Center of Immuno-Oncology and Translational Cell Therapy (KITZ), Charité-University Hospital, 10117 Berlin, Germany
| | - Siraj M. El Jamal
- Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA;
| | - Youssef Haikel
- Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France;
- Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France
- Pôle de Médecine et Chirurgie Bucco-Dentaire, Hôpital Civil, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France
| | - Mossad Megahed
- Clinic of Dermatology, University Hospital of Aachen, 52074 Aachen, Germany;
| |
Collapse
|
|
2
|
Fu X, Wang Y, Lu Y, Liu J, Li H. Association between metabolic syndrome and benign prostatic hyperplasia: The underlying molecular connection. Life Sci 2024; 358:123192. [PMID: 39488266 DOI: 10.1016/j.lfs.2024.123192] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 10/08/2024] [Accepted: 10/27/2024] [Indexed: 11/04/2024]
Abstract
Benign prostatic hyperplasia (BPH), a common cause of lower urinary tract symptoms (LUTS), has been recently regarded as a metabolic disease. Metabolic syndrome (MetS) is a constellation of metabolic disarrangements, including insulin resistance, obesity, hypertension, and dyslipidemia, and it has been established that these components of MetS are important contributing factors exacerbating the degree of prostatic enlargement and bladder outlet obstruction among patients with BPH. Clinical and experimental studies demonstrated that many molecules, such as insulin, insulin-like growth factor 1 (IGF-1), androgen and estrogen, and adipokines, are involved in the overlapping pathogenesis of BPH and MetS, indicating that clinicians might be able to simultaneously alleviate or cure two diseases by choosing appropriate medications. This article aims to systematically review the pathophysiological aspect and traditional etiology and pathogenesis of BPH and discuss the intricate association between MetS and BPH from the molecular point of view, in an attempt to provide stronger evidence for better treatment of two diseases.
Collapse
Affiliation(s)
- Xun Fu
- Department of Urology, Peking Union Medical Collage Hospital, Beijing, China
| | - Yutao Wang
- Department of Urology, Peking Union Medical Collage Hospital, Beijing, China
| | - Yi Lu
- Department of Urology, Peking Union Medical Collage Hospital, Beijing, China
| | - Jiang Liu
- Department of Urology, Peking Union Medical Collage Hospital, Beijing, China
| | - Hongjun Li
- Department of Urology, Peking Union Medical Collage Hospital, Beijing, China.
| |
Collapse
|
|
3
|
Matzkin ME, Beguerie C, De Zuñiga I, Martinez G, Frungieri MB. Impact of COVID-19 on sperm quality and the prostaglandin and polyamine systems in the seminal fluid. Andrology 2024; 12:1078-1095. [PMID: 37873918 DOI: 10.1111/andr.13548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/15/2023] [Accepted: 10/12/2023] [Indexed: 10/25/2023]
Abstract
BACKGROUND The implications of SARS-CoV-2 infection on male fertility remain largely unknown. Besides their well-known pro- and anti-inflammatory actions, prostaglandins and polyamines are present in semen, where they play key roles in sperm quality. OBJECTIVES To analyze semen parameters, oxidative profile and the seminal fluid prostaglandin and polyamine systems in samples collected from individuals without coronavirus disease 2019 diagnosis and men who recovered from coronavirus disease 2019. MATERIALS AND METHODS This study compared semen collected from men without positive coronavirus disease 2019 diagnosis with samples obtained from individuals 1-6 months and 7-30 months post SARS-CoV-2 infection. Semen parameters, thiobarbituric acid reactive substances, cyclooxygenase 2 expression by fluorescence immunocytochemistry and immunoblotting, prostaglandin levels by enzyme immunoassay, ornithine decarboxylase activity by a radioactive assay, and polyamine and acetylated polyamine levels by thin-layer chromatography were assessed. RESULTS In both groups of semen samples from coronavirus disease 2019 recovered men, sperm vitality, total and progressive sperm motility, and putrescine levels were significantly decreased when compared with samples from the uninfected group. In contrast, lipid peroxidation, leukocyte-associated cyclooxygenase 2 expression, and prostaglandin D2 levels were higher in semen from coronavirus disease 2019 recovered men than in samples from uninfected individuals. While sperm concentration and morphology, ornithine decarboxylase activity, and N-acetylputrescine levels were statistically diminished in semen obtained up to 6 months after coronavirus disease 2019 recovery, these parameters remained unchanged when samples were collected 7-30 months after coronavirus disease 2019 recovery. Coronavirus disease 2019 vaccination did not show negative effects on any of the parameters evaluated. DISCUSSION AND CONCLUSION Our work provides insights into the detrimental impact of coronavirus disease 2019 on several sperm parameters, in some cases, even more than a year after SARS-CoV-2 infection, which would be accompanied by alterations in the seminal fluid prostaglandin and polyamine profiles. Therefore, future treatments targeting the prostaglandin and polyamine pathways in coronavirus disease 2019 recovered men could lead to a successful reinstatement of semen parameters.
Collapse
Affiliation(s)
- María Eugenia Matzkin
- Laboratorio de Neuro-inmuno-endocrinología testicular, Instituto de Biología y Medicina Experimental (IBYME), Fundación IBYME, CONICET, Ciudad de Buenos Aires, Argentina
- Cátedra 1, Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina
| | - Celina Beguerie
- Fertilis Medicina Reproductiva, San Isidro, Buenos Aires, Argentina
| | | | - Gustavo Martinez
- Fertilis Medicina Reproductiva, San Isidro, Buenos Aires, Argentina
| | - Mónica Beatriz Frungieri
- Laboratorio de Neuro-inmuno-endocrinología testicular, Instituto de Biología y Medicina Experimental (IBYME), Fundación IBYME, CONICET, Ciudad de Buenos Aires, Argentina
- Cátedra de Química, Ciclo Básico Común, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina
| |
Collapse
|
|
4
|
Kopp W. Aging and "Age-Related" Diseases - What Is the Relation? Aging Dis 2024; 16:1316-1346. [PMID: 39012663 PMCID: PMC12096902 DOI: 10.14336/ad.2024.0570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 06/28/2024] [Indexed: 07/17/2024] Open
Abstract
The study explores the intricate relationship between aging and the development of noncommunicable diseases [NCDs], focusing on whether these diseases are inevitable consequences of aging or primarily driven by lifestyle factors. By examining epidemiological data, particularly from hunter-gatherer societies, the study highlights that many NCDs prevalent in modern populations are rare in these societies, suggesting a significant influence of lifestyle choices. It delves into the mechanisms through which poor diet, smoking, and other lifestyle factors contribute to systemic physiological imbalances, characterized by oxidative stress, insulin resistance and hyperinsulinemia, and dysregulation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the immune system. The interplay between this pattern and individual factors such as genetic susceptibility, biological variability, epigenetic changes and the microbiome is proposed to play a crucial role in the development of a range of age-related NCDs. Modified biomolecules such as oxysterols and advanced glycation end products also contribute to their development. Specific diseases such as benign prostatic hyperplasia, Parkinson's disease, glaucoma and osteoarthritis are analyzed to illustrate these mechanisms. The study concludes that while aging contributes to the risk of NCDs, lifestyle factors play a crucial role, offering potential avenues for prevention and intervention through healthier living practices. One possible approach could be to try to restore the physiological balance, e.g. through dietary measures [e.g. Mediterranean diet, Okinawan diet or Paleolithic diet] in conjunction with [a combination of] pharmacological interventions and other lifestyle changes.
Collapse
Affiliation(s)
- Wolfgang Kopp
- Retired head of the Diagnostikzentrum Graz, Mariatrosterstrasse 41, 8043 Graz, Austria
| |
Collapse
|
|
5
|
Shimizu S. Insights into the associative role of hypertension and angiotensin II receptor in lower urinary tract dysfunction. Hypertens Res 2024; 47:987-997. [PMID: 38351189 DOI: 10.1038/s41440-024-01597-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/05/2024] [Accepted: 01/13/2024] [Indexed: 02/16/2024]
Abstract
In men, the lower urinary tract comprises the urinary bladder, urethra, and prostate, and its primary functions include urine storage and voiding. Hypertension is a condition that causes multi-organ damage and an age-dependent condition. Hypertension and the renin-angiotensin system activation are associated with the development of lower urinary tract dysfunction. Hypertensive animal models show bladder dysfunction, urethral dysfunction, and prostatic hyperplasia. In the renin-angiotensin system, angiotensin II and the angiotensin II type 1 receptor, which are expressed in the lower urinary tract, have been implicated in the pathogenesis of lower urinary tract dysfunction. Moreover, among the several antihypertensives, renin-angiotensin system inhibitors have proven effective in human and animal models of lower urinary tract dysfunction. This review aimed to elucidate the hitherto known mechanisms underlying the development of lower urinary tract dysfunction in relation to hypertension and the angiotensin II/angiotensin II type 1 receptor axis and the effect of renin-angiotensin system inhibitors on lower urinary tract dysfunction. Possible mechanisms through which hypertension or activation of Ang II/AT1 receptor axis causes LUTD such as bladder dysfunction, urethral dysfunction, and prostatic hyperplasia. LUT: lower urinary tract, LUTD: lower urinary tract dysfunction, AT1: angiotensin II type 1, ACE: angiotensin-converting enzyme.
Collapse
Affiliation(s)
- Shogo Shimizu
- Department of Pharmacology, Kochi Medical School, Kochi University, Kohasu, Okocho, Nankoku, 783-8505, Japan.
| |
Collapse
|
|
6
|
Balacescu MS, Ene CV, Georgescu DE, Bulai CA, Militaru A, Ene CD, Vacaroiu IA, Georgescu DA, Geavlete BF, Geavlete P. The Impact of SARS-CoV-2 on Patients With Lower Urinary Tract Symptoms (LUTS). Cureus 2024; 16:e59148. [PMID: 38803716 PMCID: PMC11129723 DOI: 10.7759/cureus.59148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/27/2024] [Indexed: 05/29/2024] Open
Abstract
INTRODUCTION During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the management of patients with lower urinary tract symptoms (LUTS) underwent dynamic adjustments in response to an evolving understanding of the virus's impact on different patient populations. Healthcare practitioners reevaluated therapeutic approaches for conditions like benign prostatic hyperplasia (BPH), considering the potential implications of this condition on the severity and progression of coronavirus disease 2019 (COVID-19). This study aims to investigate potential correlations between SARS-CoV-2 infection severity, exacerbation of LUTS, and BPH progression. MATERIAL AND METHODS This retrospective study includes patients hospitalized in our Urology Department between January 2021 and January 2023, presenting with both SARS-CoV-2 and BPH. Their ages ranged from 57 to 88 years, with a mean age of 65.4 years. The diagnosis of BPH relied on a diagnostic triad consisting of digital rectal examination, biological markers (including prostate-specific antigen (PSA) and free PSA, and ultrasound examination, with both conditions confirmed based on test results. Transurethral resection of the prostate (TURP) procedures utilized monopolar Karl Storz resection equipment, using sorbitol and bipolar Olympus devices for transurethral resection of the prostate in saline (TURPis). Haemostasia was performed using roller balls. Anticoagulation followed a prescribed scheme by cardiologists and infectious disease specialists. Statistical analysis was conducted using IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp. RESULTS Among the 138 hospitalized patients affected by both BPH and COVID-19, 18 required emergency endoscopic procedures (specifically TURP or TURPis) to achieve hemostasis (Figures 1, 2). These individuals presented persistent hematuria despite conservative treatments. The mean duration of surgery was 57.9 minutes. Patients who underwent surgery had a longer average hospital stay compared to those who did not, with durations of 10.5 days versus 7.5 days, respectively. Additionally, urethrovesical catheter insertion was necessary in 29 cases due to acute urinary retention or worsening voiding symptoms during hospitalization. These patients are scheduled for further urological evaluation following the resolution of the COVID-19 episode. In a cohort of 53 patients for whom data were accessible, comparisons were made between the pre-COVID status and the levels of the International Prostate Symptom Score (IPSS), post-voiding residue (PVR), and quality of life (QoL). The findings revealed a mean pre-COVID IPSS value of 11.6 and a COVID-related value of 14.2, with a statistically significant difference noted (p < 0.05). The mean pre-COVID PVR was 42.3 cm2, whereas during the COVID-19 period, it measured 62.5 cm2, also exhibiting a significant difference (p < 0.05). Additionally, the QoL showed a mean pre-COVID-19 score of 2.4 and a COVID-19-associated score of 2.9, again demonstrating statistical significance (p < 0.05). CONCLUSION The onset of the SARS-CoV-2 pandemic posed novel challenges in the medical realm, impacting the approach to BPH management. A common practice was delaying treatment for chronic BPH until viral infection remission to reduce associated risks. Additionally, our study revealed a worse evolution in LUTS among individuals with severe COVID-19 symptoms.
Collapse
Affiliation(s)
- Marian S Balacescu
- Urology, Carol Davila University of Medicine and Pharmacy, Bucharest, ROU
- Urology, "Sf. Ioan" Clinical Emergency Hospital, Bucharest, ROU
| | - Cosmin V Ene
- Urology, Carol Davila University of Medicine and Pharmacy, Bucharest, ROU
- Urology, "Sf. Ioan" Clinical Emergency Hospital, Bucharest, ROU
| | - Dragos Eugen Georgescu
- General Surgery, Carol Davila University of Medicine and Pharmacy, Bucharest, ROU
- General Surgery, Dr. I. Cantacuzino Clinical Hospital, Bucharest, ROU
| | - Catalin A Bulai
- Urology, Carol Davila University of Medicine and Pharmacy, Bucharest, ROU
- Urology, "Sf. Ioan" Clinical Emergency Hospital, Bucharest, ROU
| | - Adrian Militaru
- Urology, Carol Davila University of Medicine and Pharmacy, Bucharest, ROU
- Urology, "Sf. Ioan" Clinical Emergency Hospital, Bucharest, ROU
| | - Corina D Ene
- Nephrology, Carol Davila University of Medicine and Pharmacy, Bucharest, ROU
- Nephrology, "Dr. Carol Davila" Clinical Nephrology Hospital, Bucharest, ROU
| | - Ileana Adela Vacaroiu
- Nephrology, Carol Davila University of Medicine and Pharmacy, Bucharest, ROU
- Nephrology, "Sf. Ioan" Clinical Emergency Hospital, Bucharest, ROU
| | - Dragos A Georgescu
- Urology, Carol Davila University of Medicine and Pharmacy, Bucharest, ROU
- Urology, "Sf. Ioan" Clinical Emergency Hospital, Bucharest, ROU
| | - Bogdan F Geavlete
- Urology, Carol Davila University of Medicine and Pharmacy, Bucharest, ROU
- Urology, "Sf. Ioan" Clinical Emergency Hospital, Bucharest, ROU
| | - Petrisor Geavlete
- Urology, Carol Davila University of Medicine and Pharmacy, Bucharest, ROU
- Urology, "Sf. Ioan" Clinical Emergency Hospital, Bucharest, ROU
| |
Collapse
|
|
7
|
Rago V, Perri A. SARS-CoV-2 Infection and the Male Reproductive System: A Brief Review. Life (Basel) 2023; 13:life13020586. [PMID: 36836943 PMCID: PMC9966870 DOI: 10.3390/life13020586] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/09/2023] [Accepted: 02/18/2023] [Indexed: 02/22/2023] Open
Abstract
Many studies have suggested that SARS-CoV-2, directly or indirectly, can affect the male reproductive system, although the underlined mechanisms have not been completely elucidated yet. The purpose of this review is to provide a summary of the current data concerning the impact of SARS-CoV-2 infection on the male urogenital tract, with a particular emphasis on the testes and male fertility. The main data regarding the morphological alterations in the testes emerged from autoptic studies that revealed interstitial congestion, micro thrombosis, reduction of Sertoli, Leydig, and germinal cells, infiltrated immune cells, and atrophic seminiferous tubules consistent with orchitis. Furthermore, men with severe infection exhibit sperm parameter alterations, together with abnormalities of the hypothalamic-pituitary-testis axis, strongly suggesting that SARS-CoV-2 could increase the risk of male infertility. However, despite the inadequate number of longitudinal studies, spermatogenesis and sex hormone imbalance seem to improve after infection resolution. The yet unresolved question is whether the virus acts in a direct or/and indirect manner, as discordant data related to its presence in the testis and semen have been reported. Regardless of the direct effect, it has been postulated that the cytokine storm and the related local and systemic inflammation could strongly contribute to the onset of testis dysfunction, leading to male infertility. Therefore, multicentric and longitudinal studies involving a large number of patients are needed to understand the real impact of SARS-CoV-2 infection on male reproduction.
Collapse
Affiliation(s)
- Vittoria Rago
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy
- Correspondence: ; Tel.: +39-0984-496210; Fax: +39-0984-493271
| | - Anna Perri
- Department of Experimental and Clinical Medicine, University of Catanzaro “Magna Græcia”, 88100 Catanzaro, CZ, Italy
| |
Collapse
|
|
8
|
Malik J, Ahmed S, Momin SS, Shaikh S, Alafnan A, Alanazi J, Said Almermesh MH, Anwar S. Drug Repurposing: A New Hope in Drug Discovery for Prostate Cancer. ACS OMEGA 2023; 8:56-73. [PMID: 36643505 PMCID: PMC9835086 DOI: 10.1021/acsomega.2c05821] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/24/2022] [Indexed: 06/12/2023]
Abstract
Prostate cancer (PCA), the most common cancer in men, accounted for 1.3 million new incidences in 2018. An increase in incidences is an issue of concern that should be addressed. Of all the reported prostate cancers, 85% were detected in stages III and IV, making them difficult to treat. Conventional drugs gradually lose their efficacy due to the developed resistance against them, thus requiring newer therapeutic agents to be used as monotherapy or combination. Recent research regarding treatment options has attained remarkable speed and development. Therefore, in this context, drug repurposing comes into the picture, which is defined as the "investigation of the off-patent, approved and marketed drugs for a novel therapeutic indication" which saves at least 30% of the time and cost, reducing the cost of treatment for patients, which usually runs high in cancer patients. The anticancer property of cardiac glycosides in cancers was tested in the early 1980s. The trend then shifts toward treating prostate cancer by repurposing other cardiovascular drugs. The current review mainly emphasizes the advantageous antiprostate cancer profile of conventional CVS drugs like cardiac glycosides, RAAS inhibitors, statins, heparin, and beta-blockers with underlying mechanisms.
Collapse
Affiliation(s)
- Jonaid
Ahmad Malik
- Department
of Pharmacology and Toxicology, National
Institute of Pharmaceutical Education and Research, Guwahati 781003, India
- Biomedical
Engineering, Indian Institute of Technology
(IIT), Ropar, Punjab 140001, India
| | - Sakeel Ahmed
- Department
of Pharmacology and Toxicology, National
Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat 382355, India
| | - Sadiya Sikandar Momin
- Department
of Pharmaceutics, Annasaheb Dange College of B. Pharmacy, Ashta, Shivaji University, Sangli, Maharastra 416301, India
| | - Sijal Shaikh
- Sandip Institute
of Pharmaceutical Sciences, Savitribai Phule
Pune University, Nashik, Maharashtra 422213, India
| | - Ahmed Alafnan
- Department
of Pharmacology and Toxicology, University
of Hail, Hail 81422, Saudi Arabia
| | - Jowaher Alanazi
- Department
of Pharmacology and Toxicology, University
of Hail, Hail 81422, Saudi Arabia
| | | | - Sirajudheen Anwar
- Department
of Pharmacology and Toxicology, University
of Hail, Hail 81422, Saudi Arabia
| |
Collapse
|
|
9
|
Lin L, Li P, Liu X, Xie X, Liu L, Singh AK, Singh HN. Systematic review and meta-analysis of candidate gene association studies of benign prostate hyperplasia. Syst Rev 2022; 11:60. [PMID: 35382870 PMCID: PMC8985373 DOI: 10.1186/s13643-022-01914-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 03/03/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Benign prostate hyperplasia (BPH) is the most common urological problem in elderly males. Recent studies have reported polymorphism in various metabolic genes in BPH. However, their association with the susceptibility of BPH is still inconsistent. Here, we systematically reviewed and performed a meta-analysis of CYP17, VDR, and ACE genes to determine their precise association with the risk of BPH. METHODS A comprehensive literature search for published studies on candidate gene associations involving vitamin D receptor (VDR), angiotensin-converting enzyme (ACE), and CYP17 genes with the risk of BPH was done up to April 2020 in PubMed, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar databases. Fixed/random effects models were used to estimate the odd's ratio (OR) and 95% confidence intervals (CIs). Begg's funnel plot was used to assess the potential for publication bias. RESULTS We found a total of 23 studies containing 3461 cases and 3833 controls for these gene polymorphisms. A significant association of ACE gene polymorphism was observed under the recessive (II vs. ID + DD) model for BPH susceptibility compared to control subjects (overall OR = 1.67, 95% CI = 1.03-2.73). Similar trends were observed for ACE gene polymorphism in Caucasian (OR = 6.18, 95% CI = 1.38-27.68) and Asian (OR = 1.42, 95% CI = 0.99-2.03) populations under study. No significant association was observed in VDR and CYP17 gene polymorphisms in any dominant or recessive models. CONCLUSION Significant OR demonstrated the implication of ACE gene polymorphism in the proliferation of prostate tissue, which in turn is associated with BPH susceptibility. However, prospective studies at large scale and sample size are needed to confirm the current findings.
Collapse
Affiliation(s)
- Lin Lin
- Department of Urology, Hospital of Traditional Chinese and Western Medicine of Taizhou, Taizhou, 317502, Zhejiang, China
| | - Pugui Li
- Department of Urology, Tangdu Hospital,Air Force Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xin Liu
- Department of Critical Care Medicine, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi Municipality, 830000, Xinjiang, China
| | - Xiuyuan Xie
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing City, 210029, Jiangsu, China
| | - Liping Liu
- Department of Outpatient, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou City, 510260, Guangdong, China.
| | - Anjani Kumar Singh
- Department of Physics, Atma Ram Sanatan Dharma College, University of Delhi, New Delhi, India
| | | |
Collapse
|
|
10
|
Haghpanah A, Masjedi F, Salehipour M, Hosseinpour A, Roozbeh J, Dehghani A. Is COVID-19 a risk factor for progression of benign prostatic hyperplasia and exacerbation of its related symptoms?: a systematic review. Prostate Cancer Prostatic Dis 2022; 25:27-38. [PMID: 34007019 PMCID: PMC8129694 DOI: 10.1038/s41391-021-00388-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND To explore the potential mechanisms of SARS-CoV-2 in targeting the prostate gland, leading to exacerbation of benign prostatic hyperplasia (BPH) symptoms and greater risks of BPH complications such as acute urinary retention. METHODS A categorized and comprehensive search in the literature has been conducted by 10 April 2021 using international databases including PubMed, Embase, Web of Science, Scopus, and Cochrane Library in line with the PRISMA guidelines recommendations. PICO strategy was used to formulate the research question. The following terms were used: urology, COVID-19, coronavirus, BPH, inflammation, androgen receptors, LUTS, IPSS, PSA, and SARS-CoV-2 or a combination of them. Studies with irrelevant purposes and duplicates were excluded. The selected studies were performed on humans and published in English. RESULTS The research revealed 89 articles. After title screening and considering exclusion criteria, 52 papers were included for the systematic review. BPH is a common condition affecting older men. SARS-CoV-2 infects the host cell by binding to angiotensin converting enzyme 2 (ACE2). A hyperactivated RAS system during infection with SARS-CoV-2 may lead to activation of pro-inflammatory pathways and increased cytokine release. Thus, this virus can lead to exacerbation of lower urinary tract symptoms (LUTS) and trigger inflammatory processes in the prostate gland. Since androgen receptors (AR) play an important role in the BPH pathophysiology and infection with SARS-CoV-2 may be androgen-mediated, BPH progression and its related symptoms can be a complication of COVID-19 through AR involvement and metabolic disturbances. CONCLUSIONS Based on the current findings, SARS-CoV-2 can possibly damage the prostate and worsen BPH and its related LUTS through ACE2 signaling, AR-related mechanisms, inflammation, and metabolic derangement. We encourage future studies to investigate the possible role of COVID-19 in the progression of BPH-related LUTS and examine the prostatic status in susceptible patients with relevant available questionnaires (e.g., IPSS) and serum biomarkers (e.g., PSA).
Collapse
Affiliation(s)
- Abdolreza Haghpanah
- grid.412571.40000 0000 8819 4698Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran ,grid.412571.40000 0000 8819 4698Department of Urology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Masjedi
- grid.412571.40000 0000 8819 4698Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehdi Salehipour
- grid.412571.40000 0000 8819 4698Department of Urology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Hosseinpour
- grid.412571.40000 0000 8819 4698Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran ,grid.412571.40000 0000 8819 4698Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jamshid Roozbeh
- grid.412571.40000 0000 8819 4698Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Anahita Dehghani
- grid.412571.40000 0000 8819 4698Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| |
Collapse
|
|
11
|
Variation of Serum PSA Levels in COVID-19 Infected Male Patients with Benign Prostatic Hyperplasia (BPH): A Prospective Cohort Studys. Urology 2021; 159:16-21. [PMID: 34626600 PMCID: PMC8493783 DOI: 10.1016/j.urology.2021.09.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/26/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To investigate the effect of SARS CoV-2 on serum total PSA levels in men with BPH diagnosed with COVID-19. METHODS The PSA (Kit: Immunoassay Program- Cycle 18, Siemens Atellica IM Analyzer) levels in patients who had had a PSA check at least 3 months, but no more than 6 months, prior to diagnosis of acute COVID-19 infection, were examined retrospectively. PSA levels were measured and recorded from these patients on the first day of diagnosis of COVID-19. These patients were called back for urology outpatient follow-up at the third month after the end of the COVID-19 treatment. PSA levels measured in the pre-COVID-19 period, during the period of active infection with COVID-19, and in the post-COVID-19 period were compared. RESULTS In total, 91 patients had a serum PSA level of 1.58 ± 1.09 ng/mL in the pre-COVID-19 period, a serum PSA level of 4.34 ± 3.78 ng/mL measured in the COVID-19 period and 2.09 ± 2.70 ng/mL in the post-COVID-19 period. It was determined that the serum PSA level measured during active COVID-19 infection was statistically significantly higher than the PSA levels measured according to the pre-COVID-19 period and the post-COVID-19 period (P < .001, P < .001; respectively). CONCLUSION SARS-CoV-2 infection in men diagnosed with BPH causes significant increases in PSA levels during the active period of the disease. Measurement of PSA values used in the diagnosis, differential diagnosis, and follow-up of prostate diseases in the acute period of infection and in the early period after infection treatment may cause false evaluations that may affect the diagnosis and treatment steps of prostate diseases in these patients.
Collapse
|
|
12
|
Oxidative Stress Links Aging-Associated Cardiovascular Diseases and Prostatic Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5896136. [PMID: 34336107 PMCID: PMC8313344 DOI: 10.1155/2021/5896136] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/17/2021] [Accepted: 07/03/2021] [Indexed: 11/29/2022]
Abstract
The incidence of chronic aging-associated diseases, especially cardiovascular and prostatic diseases, is increasing with the aging of society. Evidence indicates that cardiovascular diseases usually coexist with prostatic diseases or increase its risk, while the pathological mechanisms of these diseases are unknown. Oxidative stress plays an important role in the development of both cardiovascular and prostatic diseases. The levels of oxidative stress biomarkers are higher in patients with cardiovascular diseases, and these also contribute to the development of prostatic diseases, suggesting cardiovascular diseases may increase the risk of prostatic diseases via oxidative stress. This review summarizes the role of oxidative stress in cardiovascular and prostatic diseases and also focuses on the main shared pathways underlying these diseases, in order to provide potential prevention and treatment targets.
Collapse
|
|
13
|
Hypertension, cardiovascular disease, and nocturia: a systematic review of the pathophysiological mechanisms. Hypertens Res 2021; 44:733-739. [PMID: 33654248 DOI: 10.1038/s41440-021-00634-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 01/27/2021] [Accepted: 01/27/2021] [Indexed: 01/31/2023]
Abstract
Nocturia significantly impairs quality of life, especially in the elderly population, and urinary retention is a main target of treatment for urologists. In addition to nocturia, cardiovascular diseases are common in the elderly population, and a systematic review showed that hypertension and heart failure are often associated with nocturia. One possible pathogenic mechanism underlying the development of hypertension is an increase in blood pressure due to excessive salt intake in people with high-salt sensitivity. From Guyton's natriuretic curve, we can infer that salt-sensitive hypertensive patients who consume too much salt do not excrete salt during the daytime and are forced to excrete salt at night, resulting in increased urine production and nocturia. In patients with heart failure, the nocturnal supine position leads to an increase in central fluid volume due to an increase in venous return from the periphery, and the secretion of natriuretic peptide is stimulated by the stretching of the atria and ventricles. Thus, natriuresis due to hypertension and hydrodiuresis due to heart failure may cause nocturia, which can effectively be treated by the administration of thiazide diuretics and loop diuretics in the morning, respectively. Because cardiovascular diseases, such as hypertension and heart failure, can cause nocturia and because the treatment methods differ depending on the cause, it is necessary to pay close attention to nocturia in the management of lifestyle-related diseases, such as cardiovascular disease.
Collapse
|
|
14
|
Shimizu S, Nagao Y, Shimizu T, Higashi Y, Karashima T, Saito M. Therapeutic effects of losartan on prostatic hyperplasia in spontaneously hypertensive rats. Life Sci 2020; 266:118924. [PMID: 33352172 DOI: 10.1016/j.lfs.2020.118924] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 12/04/2020] [Accepted: 12/12/2020] [Indexed: 11/30/2022]
Abstract
AIMS We investigated the therapeutic effects of losartan, an angiotensin II type 1 receptor blocker, on prostatic hyperplasia in spontaneously hypertensive rats (SHRs). MAIN METHODS Male SHRs (age, 36 weeks) were perorally treated with losartan (3 or 10 mg·kg-1) or vehicle once daily for 18 weeks. Age-matched Wistar Kyoto rats (WKYs) were used as vehicle-treated controls (n = 8). The effects of losartan were evaluated by analyzing prostate weight, blood pressure, and prostatic blood flow. The tissue malondialdehyde (MDA), interleukin-6 (IL-6), and basic fibroblast growth factor (bFGF) levels were measured. Histological analysis for the ventral prostate involved hematoxylin and eosin staining and TdT-mediated dUTP nick-end labeling (TUNEL) assay. KEY FINDINGS Compared to the vehicle-treated WKYs, the vehicle-treated SHRs had significantly higher prostate weight, prostate weight/body weight ratio (PBR), blood pressure, glandular epithelial area, and tissue MDA, IL-6, and bFGF levels in the ventral prostate and lower prostatic blood flow. Treatment with losartan caused significant recovery of blood flow and decreased PBR and glandular epithelial area as well as tissue MDA, IL-6, and bFGF levels in the SHR ventral prostate without affecting blood pressure. High-dose losartan significantly decreased blood pressure and increased TUNEL-positive cells in the ventral prostate in SHRs. SIGNIFICANCE Chronic losartan treatment could ameliorate prostatic hyperplasia via recovery of reduced prostatic blood flow and induction of apoptosis in the ventral prostate in SHRs. Losartan might have therapeutic effects on not only hypertension but also prostatic hyperplasia in humans.
Collapse
Affiliation(s)
- Shogo Shimizu
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Yoshiki Nagao
- Department of Pediatrics, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Takahiro Shimizu
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Youichirou Higashi
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Takashi Karashima
- Department of Urology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Motoaki Saito
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan.
| |
Collapse
|
|
15
|
Noh JW, Kim KB, Kwon YD, Kim JH. Association between sodium intake and lower urinary tract symptoms: does less sodium intake have a favorable effect or not? Transl Androl Urol 2020; 9:1135-1145. [PMID: 32676397 PMCID: PMC7354310 DOI: 10.21037/tau-19-808] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Background Sodium intake is known to be related with hypertension (HTN), which could impact lower urinary tracts symptoms (LUTS) indirectly. To date, only limited clinical evidences exist upon the association between sodium preference and LUTS. This cross-sectional study analyzed the association between sodium preference and the severity of LUTS in men. Methods A cross-sectional analysis has been performed and a total of 86,637 participants among total registered population of 229,226 in Korean Community Health Survey (KCHS) were included for final analysis. The adjusted odds ratio (OR) or coefficient with 95% confidence interval (CI) estimates were described to show the association between sodium preference and LUTS using negative binomial regression (for the IPSS total, IPSS voiding, and IPSS storage symptoms), ordinal logistic regression (for the IPSS grade), and binomial logistic regression (for the IPSS nocturia symptoms). Results Preference of salty taste group (high sodium preference) were significantly associated with higher IPSS total score (Coef =0.31; 95% CI: 0.27, 0.35), increased risk of severe IPSS grade (OR =1.46; 95% CI: 1.35, 1.57), higher IPSS voiding score (Coef =0.38; 95% CI: 0.32, 0.44), higher IPSS storage score (Coef =0.25; 95% CI: 0.22, 0.29), and increased risk of having IPSS nocturia symptoms (OR =1.21; 95% CI: 1.16, 1.27) compared to subjects with neutral group (normal sodium preference). Prediction of IPSS score according to salty taste preference showed u shaped distribution. Conclusions Sodium preference for taste were significantly associated with LUTS including voiding symptom, storage symptom and nocturia. Both higher and lower intake of sodium could be unfavorable factor for severity of LUTS.
Collapse
Affiliation(s)
- Jin-Won Noh
- Department of Health Administration, Dankook University, Cheonan, Korea
| | - Kyoung-Beom Kim
- Department of Health Administration, Dankook University, Cheonan, Korea
| | - Young Dae Kwon
- Department of Humanities and Social Medicine, College of Medicine and Catholic Institute for Healthcare Management, The Catholic University of Korea, Seoul, Korea
| | - Jae Heon Kim
- Department of Urology, Soonchunhyang University Hospital, Soonchuhyang University Medical College, Seoul, Korea
| |
Collapse
|
|
16
|
Mostafa F, Mantawy EM, Azab SS, El-Demerdash E. The angiotensin converting enzyme inhibitor captopril attenuates testosterone-induced benign prostatic hyperplasia in rats; a mechanistic approach. Eur J Pharmacol 2019; 865:172729. [PMID: 31605676 DOI: 10.1016/j.ejphar.2019.172729] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 10/04/2019] [Accepted: 10/07/2019] [Indexed: 12/13/2022]
Abstract
Benign prostatic hyperplasia (BPH) is the most widespread urological disorder among elderly men. It is influenced by several factors, among which is the prostatic renin angiotensin system (RAS). Prostatic RAS activates several signaling pathways as proliferation, inflammation and angiogenesis that contribute to BPH development and progression. Captopril is a potent inhibitor of the angiotensin converting enzyme. Therefore, this study was performed to explore the potential protective effect of captopril against testosterone-induced BPH in rats. Male Sprague-Dawley rats were treated with either testosterone (3 mg/kg, s. c.) and/or captopril (100 mg/kg, orally) for four weeks. After treatments, prostatic serum markers and histopathology were assessed. Mechanistically, apoptotic, inflammatory and angiogenic pathways were examined. Testosterone significantly increased prostate weight, prostatic index, prostatic acid phosphatase and prostate specific antigen. These effects were almost prevented by captopril (100 mg/kg). Moreover, testosterone significantly elevated proliferating cell nuclear antigen and reduced Bax/Bcl-2 ratio, p53 and caspase-3 activity. Furthermore, it significantly elevated nuclear factor kappa-B, cyclooxygenase-II, tumor necrosis factor-α and interleukin-8. Besides, it caused a significant rise in vascular endothelial growth factor, basic fibroblast growth factor and matrix metalloproteinase-9. On the contrary, captopril effectively neutralised the proliferative, inflammatory and angiogenic effects of testosterone. Finally, the angiotensin-1 receptor expression in the BPH group was markedly decreased while captopril restored the receptor expression. Collectively, these findings indicate that captopril possesses a potent protective effect against testosterone-induced BPH via inducing apoptotic and suppressing inflammatory and angiogenic signaling pathways.
Collapse
Affiliation(s)
- Fatma Mostafa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Eman M Mantawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Samar S Azab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Ebtehal El-Demerdash
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
| |
Collapse
|
|
17
|
Jain A, Shah H, Simonsick EM, Metter EJ, Mangold L, Humphreys E, Partin A, Fedarko NS. Angiotensin receptor autoantibodies as exposures that modify disease progression: Cross sectional, longitudinal and in vitro studies of prostate cancer. J Transl Autoimmun 2019; 2:100008. [PMID: 31930191 PMCID: PMC6953913 DOI: 10.1016/j.jtauto.2019.100008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 07/28/2019] [Accepted: 07/29/2019] [Indexed: 12/23/2022] Open
Abstract
Circulating angiotensin type I receptor (AT1R) agonistic autoantibodies (AT1RaAbs) that bind and chronically activate the receptor have been associated with a number of diseases suggesting that while the autoantibodies are not necessarily causative they may promote disease progression. The prostate has a local renin angiotensin system. The current study examines associations between AT1RaAbs and prostate cancer (PCA), disease-free survival (DFS), overall survival (OS) and AT1RaAb effects on PCA cell phenotype. In a cross-sectional set of serum obtained from 151 men diagnosed with PCA, nonmalignant prostate disease or no disease, higher serum AT1RaAb levels were associated with PCA and non-organ confined PCA. The odds ratio for PCA was 6.3 (95% confidence interval 2.2 to 18) for a positive 1:1600 titer and 18 (95% confidence interval 6.9 to 45) at AT1RaAb levels > 1.04 μg/ml, (p < 0.0001). In a longitudinal set of pre-diagnosis samples from 109 men, DFS hazard ratios of 2.2 (95% confidence interval 1.4 to 3.5) and 1.6 (95% confidence interval 1.0 to 2.5) for most proximal to diagnosis and most distal to diagnosis samples, respectively, were found for high versus low AT1RaAb groups. Hazard ratios for OS in most proximal and distal samples were 2.4 (95% confidence interval 1.6 to 3.6) and 1.8 (95% confidence interval 1.1 to 2.8), respectively. Accelerated failure modeling of survival indicated that a 1 μg/ml increase in AT1RaAb levels was associated with a reduction of DFS and OS by 20% at the most proximal time point and by 15% at the most distal time points. Adjusting for age, did not affect the association with DFS in proximal samples but changed distal time point DFS and OS to a 10% decrease for every 1 μg/ml increase in AT1RaAb. Additional adjustments for body mass index, systolic blood pressure and prostate-specific antigen did not appreciably alter these associations. AT1RaAb treatment of PC3, DU145, and LNCaP cells significantly increased the maximal growth rate approximately 2-fold and invasiveness approximately 3-fold. Conclusions: These observations provide evidence supporting AT1RaAbs as exposures that may modify prostate cancer progression and indicate they may be predictive markers for risk stratification.
Collapse
Affiliation(s)
- Alka Jain
- Department of Medicine, Johns Hopkins University, Baltimore, MD, 21224, USA
| | - Haikoo Shah
- Department of Medicine, Johns Hopkins University, Baltimore, MD, 21224, USA
- Department of Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Eleanor M. Simonsick
- Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21225, USA
| | - E. Jeffrey Metter
- Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21225, USA
- Current Address: Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Leslie Mangold
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Elizabeth Humphreys
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Alan Partin
- Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Neal S. Fedarko
- Department of Medicine, Johns Hopkins University, Baltimore, MD, 21224, USA
| |
Collapse
|
|
18
|
Siltari A, Murtola TJ, Talala K, Taari K, Tammela TLJ, Auvinen A. Antihypertensive drugs and prostate cancer risk in a Finnish population-based cohort. Scand J Urol 2019; 52:321-327. [PMID: 30698056 DOI: 10.1080/21681805.2018.1559882] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND The etiology of prostate cancer (PCa) involves environmental and genetic factors. Understanding the role of medication use on PCa risk may clarify the pathophysiological changes and mechanisms in development of cancer. METHODS This study investigated PCa risk in relation to overall use of anti-hypertensive drugs and those with specific mechanisms of action. The study cohort (78,615 men) was linked to the prescription database to obtain information on medication use during 20-year follow-up. Information was obtained on PCa diagnoses, causes of deaths, and for a sub-set on B.M.I. and use of non-prescription drugs. Time-dependent drug use variables hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox regression analyses. RESULTS Use of antihypertensive drugs slightly increased PCa risk (HR = 1.16, 95% CI = 1.11-1.22). The risk increase was clearest for metastatic PCa (HR = 1.36, 95% CI = 1.14-1.62). ACE inhibitors, beta-blockers, and diuretics were all separately associated with a small excess risk (HR = 1.10, 95% CI = 1.01-1.19, HR = 1.14, 95% CI = 1.06-1.21, and HR = 1.16, 95% CI = 1.07-1.27, respectively). None of the other groups showed a clear association with PCa risk. CONCLUSIONS The use of antihypertensive drugs was associated with increased prostate cancer risk. Similar risk association for multiple drug groups suggests that the findings may not reflect a direct medication effect, but may be due to underlying hypertension.
Collapse
Affiliation(s)
- Aino Siltari
- a Faculty of Medicine, Pharmacology , University of Helsinki , Helsinki , Finland.,b Faculty of Medicine and Life Sciences , University of Tampere , Tampere , Finland
| | - Teemu J Murtola
- b Faculty of Medicine and Life Sciences , University of Tampere , Tampere , Finland.,c Department of Urology , Tampere University Hospital , Tampere , Finland.,d Department of Surgery , Seinäjoki Central Hospital , Seinäjoki , Finland
| | | | - Kimmo Taari
- f Department of Urology , University of Helsinki and Helsinki University Hospital , Helsinki , Finland
| | - Teuvo L J Tammela
- b Faculty of Medicine and Life Sciences , University of Tampere , Tampere , Finland.,c Department of Urology , Tampere University Hospital , Tampere , Finland
| | - Anssi Auvinen
- g Faculty of Social Sciences , University of Tampere , Tampere , Finland
| |
Collapse
|
|
19
|
Influence and mechanism of Angiotensin 1-7 on biological properties of normal prostate epithelial cells. Biochem Biophys Res Commun 2018; 502:152-159. [DOI: 10.1016/j.bbrc.2018.05.138] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 05/18/2018] [Indexed: 12/28/2022]
|
|
20
|
Kopp W. Diet-Induced Hyperinsulinemia as a Key Factor in the Etiology of Both Benign Prostatic Hyperplasia and Essential Hypertension? Nutr Metab Insights 2018; 11:1178638818773072. [PMID: 30455570 PMCID: PMC6238249 DOI: 10.1177/1178638818773072] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Accepted: 04/04/2018] [Indexed: 01/09/2023] Open
Abstract
Benign prostatic hyperplasia and hypertension are common age-related comorbidities. Although the etiology of benign prostatic hyperplasia (BPH) is still largely unresolved and poorly understood, a significant age-independent association was found between BPH and hypertension, indicating a common pathophysiological factor for both diseases. It has previously been suggested that the development of essential hypertension may be related to diet-induced hyperinsulinemia. This study follows the question, whether BPH may develop due to the same mechanism, thereby explaining the well-known comorbidity of these 2 disorders. The scientific evidence presented shows that BPH and hypertension share the same pathophysiological changes, with hyperinsulinemia as the driving force. It further shows that significant dietary changes during human history cause disruption of a finely tuned metabolic balance that has evolved over millions of years of evolution: high-insulinemic food, typical of current “Western” diets, has the potential to cause hyperinsulinemia and insulin resistance, as well as an abnormally increased activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, alterations that play a pivotal role in the pathogenesis of BPH and hypertension.
Collapse
Affiliation(s)
- Wolfgang Kopp
- Former head of the Diagnostikzentrum Graz, Graz, Austria
| |
Collapse
|
|
21
|
Siregar S, Parardya A, Sibarani J, Romdan T, Adi K, Hernowo BS, Yantisetiasti A. AT 1 expression in human urethral stricture tissue. Res Rep Urol 2017; 9:181-186. [PMID: 28979891 PMCID: PMC5602470 DOI: 10.2147/rru.s141327] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Urethral stricture has a high recurrence rate. There is a common doctrine stating that "once a stricture, always a stricture". This fibrotic disease pathophysiology, pathologically characterized by excessive production, deposition and contraction of extracellular matrix is unknown. Angiotensin II type 1 (AT1) receptor primarily induces angiogenesis, cellular proliferation and inflammatory responses. AT1 receptors are also expressed in the fibroblasts of hypertrophic scars, whereas angiotensin II (AngII) regulates DNA synthesis in hypertrophic scar fibroblasts through a negative cross talk between AT1 and angiotensin II type 2 (AT2) receptors, which might contribute to the formation and maturation of human hypertrophic scars. OBJECTIVE This study was conducted to determine the expression of AT1 receptors in urethral stricture tissues. METHODS Urethral stricture tissues were collected from patients during anastomotic urethroplasty surgery. There were 24 tissue samples collected in this study with 2 samples of normal urethra for the control group. Immunohistochemistry study was performed to detect the presence of AT1 receptor expression. Data were analyzed using Mann-Whitney U test, and statistical analysis was performed with SPSS version 20. RESULTS This study showed that positive staining of AT1 receptor was found in all urethral stricture tissues (n=24). A total of 8.33% patients had low intensity, 41.67% had moderate intensity and 50% had high intensity of AT1 receptors, while in the control group, 100% patients had no intensity of AT1 receptors. Using the Mann-Whitney U test, it was found that urethral stricture tissue had a higher intensity of AT1 receptors than normal urethral tissue with a p-value = 0.012. CONCLUSION The results showed that AT1 receptor had a higher intensity in the urethral stricture tissue and that AT1 receptor may play an important role in the development of urethral stricture.
Collapse
Affiliation(s)
| | | | | | | | | | - Bethy S Hernowo
- Department of Pathological Anatomy, Hasan Sadikin Hospital, Faculty of Medicine University of Padjadjaran, Bandung, Indonesia
| | - Anglita Yantisetiasti
- Department of Pathological Anatomy, Hasan Sadikin Hospital, Faculty of Medicine University of Padjadjaran, Bandung, Indonesia
| |
Collapse
|
|
22
|
Domińska K, Ochędalski T, Kowalska K, Matysiak-Burzyńska ZE, Płuciennik E, Piastowska-Ciesielska AW. Interaction between angiotensin II and relaxin 2 in the progress of growth and spread of prostate cancer cells. Int J Oncol 2016; 48:2619-28. [PMID: 27035428 DOI: 10.3892/ijo.2016.3458] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 02/18/2016] [Indexed: 11/06/2022] Open
Abstract
Deregulation of locally secreted hormones, such as angiotensin II (Ang II) and relaxin 2 (RLN2), has been linked to a higher risk of select cancers or a poor prognosis in patients. In this study, for the first time a common effect of Ang II and RLN2 in relation to various aspects of prostate cancer development and metastasis are presented. Four independent colorimetric assays were used to analyze cell viability and proliferation. The changes of cell adhesion to extracellular matrix proteins and invasion/aggressiveness ability of prostate cancer cells (LNCaP, PC3) before and after peptides treatment, were also investigated. The findings suggest that the both investigated systems, have an impact on cell growth/division or spread, to some degree via overlapping signal transduction pathways. Intermediate or sometimes poorer results were achieved by using a combination of both hormones than when each was used individually. It seems that Ang II and RLN2 can play a significant role in increasing the aggressiveness of prostate tumors by up-regulating BIRC5 expression and MMP-2 and MMP-9 secretion. In addition, we speculate that Ang II and RLN2 are involved in the transition from the androgen-dependent to the androgen-independent phenotype via modulation of the expression of androgen receptors.
Collapse
Affiliation(s)
- Kamila Domińska
- Department of Comparative Endocrinology, Medical University of Lodz, 90-752 Lodz, Poland
| | - Tomasz Ochędalski
- Department of Comparative Endocrinology, Medical University of Lodz, 90-752 Lodz, Poland
| | - Karolina Kowalska
- Department of Comparative Endocrinology, Medical University of Lodz, 90-752 Lodz, Poland
| | | | - Elżbieta Płuciennik
- Department of Molecular Cancerogenesis, Medical University of Lodz, 90-752 Lodz, Poland
| | | |
Collapse
|
|
23
|
Alashkham A, Paterson C, Windsor P, Struthers A, Rauchhaus P, Nabi G. The Incidence and Risk of Biochemical Recurrence Following Radical Radiotherapy for Prostate Cancer in Men on Angiotensin-Converting Enzyme Inhibitors (ACEIs) or Angiotensin Receptor Blockers (ARBs). Clin Genitourin Cancer 2016; 14:398-405. [PMID: 27053500 DOI: 10.1016/j.clgc.2016.03.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 03/03/2016] [Accepted: 03/07/2016] [Indexed: 10/22/2022]
Abstract
BACKGROUND Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are linked to prostate cancer, but their effect on biochemical recurrence (BR) remains unknown. Our aims were to investigate the incidence and risk of BR in men on ACEIs/ARBs after radical radiotherapy with adjuvant∖neoadjuvant hormone treatment. MATERIAL AND METHODS A propensity score analysis of 558 men was conducted. Men were stratified into 3 groups: hypertensive men on ACEIs/ARBs (as a study group), non-hypertensive men not on ACEIs/ARBs, and hypertensive men not on ACEIs/ARBs (both as a control group). The multivariate analysis of variance, chi-square, Kruskal-Wallis, analysis of variance, risk ratio, confidence interval, Kaplan-Meier plots, and log-rank tests were used. RESULTS The mean age and follow-up were 68.51 and 3.33 years, respectively. There was a statistically significant difference in the prevalence of BR among the treatment groups (P < .001). The incidence of BR was significantly lower in hypertensive men taking ACEIs/ARBs than in non-hypertensive men not taking ACEIs/ARBs (P < .001) or in hypertensive men not taking ACEIs/ARBs (P < .009). The incidence of BR was significantly lower in hypertensive men not taking ACEIs/ARBs than in non-hypertensive men not taking ACEIs/ARBs (P < .013). The risk ratio (RR) of BR in the group of hypertensive men taking ACEIs/ARBs was significantly lower than in the group of non-hypertensive men not taking ACEIs/ARBs (RR, 0.74; 95% CI, 0.64-0.86; P < .001) and in the group of hypertensive men not taking ACEIs/ARBs (RR, 0.78; 95% CI, 0.67-0.91; P < .001). The time-to-event analysis revealed that the group of hypertensive men taking ACEIs/ARBs was significantly different compared with the control groups (P < .031). CONCLUSION Men who were taking ACEIs/ARBs had significantly lower incidence of BR after radical radiotherapy with hormone treatment. The intake of ACEIs/ARBs was associated with reduced risk of BR.
Collapse
Affiliation(s)
- Abduelmenem Alashkham
- Academic Section of Urology, Division of Cancer Research, School of Medicine, University of Dundee, Scotland.
| | - Catherine Paterson
- Academic Section of Urology, Division of Cancer Research, School of Medicine, University of Dundee, Scotland
| | - Phyllis Windsor
- Department of Radiation Oncology, Ninewells Hospital, National Health Service Tayside, Dundee, Scotland
| | - Allan Struthers
- Department of Cardiology, Division of Cardiovascular and Diabetes, School of Medicine, University of Dundee, Scotland
| | - Petra Rauchhaus
- Tayside Clinical Trials Unit, School of Medicine, University of Dundee, Scotland
| | - Ghulam Nabi
- Academic Section of Urology, Division of Cancer Research, School of Medicine, University of Dundee, Scotland
| |
Collapse
|
|
24
|
Ito H, Yokoyama O. Metabolic syndrome and lower urinary tract symptoms. World J Clin Urol 2014; 3:330-335. [DOI: 10.5410/wjcu.v3.i3.330] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 06/21/2014] [Accepted: 07/29/2014] [Indexed: 02/06/2023] Open
Abstract
Recently, clinical and epidemiologic data indicating the involvement of metabolic syndrome (MetS) in the pathogenesis and progression of lower urinary tract symptom (LUTS)/benign prostatic hyperplasia (BPH) are reported. This review evaluates the reports on the influence of MetS in the development and progression of LUTS/BPH, and discusses possible clinical implications for the management and treatment of this disease. Recent studies on the epidemiological relationship between MetS and LUTS hypothesize that MetS may be associated with an overactivity of the autonomic nervous system for which hyperinsulinemia, a key element of the MetS, might be responsible. An alternative explanation is that LUTS are associated with chronic ischemia of pelvis resulting from atherosclerotic changes in blood vessels, which leads the production of reactive oxygen species, which can damage the bladder detrusor. Control of autonomic nervous system overactivity and control of chronic bladder ischemia have potential as new targets for LUTS treatment. Studies suggest an association of MetS with LUTS/BPH, although further research is needed to understand how MetS influences LUTS/BPH. MetS should be considered a new domain in basic and clinical research in patients with LUTS/BPH and as a target for treatment.
Collapse
|
|
25
|
Tobu S, Noguchi M, Mori KI, Matsuo M, Uozumi J. Chronic urinary retention could decrease the number of suburothelial myofibroblasts in the rat bladder. Urol Int 2014; 92:477-81. [PMID: 24643089 DOI: 10.1159/000357118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 10/30/2013] [Indexed: 11/19/2022]
Abstract
AIMS To demonstrate changes in the number of suburothelial myofibroblasts in the rat bladder due to chronic urinary retention (CUR). METHODS Bladder specimens were obtained from 12-week-old Wistar female rats that were divided into two groups: a CUR group and a sham-operated group. In the CUR rats, the urethra was intubated with a polyethylene catheter, and a double 4-0 silk ligature was placed around the proximal urethra, after which the catheter was removed. After 8 weeks, the cystometric findings and immunohistochemical staining of the suburothelial myofibroblasts were compared between the groups. RESULTS The bladder weight of the control rats was 0.20 ± 0.01 g and that of CUR rats 1.6 ± 0.4 g. The bladder capacity of the control rats was 0.5 ± 0.3 ml and that of the CUR rats 12.9 ± 3.1 ml. The number of suburothelial myofibroblasts of the control rats was 417 ± 123 and that of the CUR rats 44 ± 42. The number of suburothelial myofibroblasts in the CUR rats was significantly less than that observed in the sham-operated rats (p < 0.01). CONCLUSIONS In this study, we demonstrated that mechanical stress over a long period on the bladder wall can decrease the number of suburothelial myofibroblasts. The reduced expression of suburothelial myofibroblasts may be related to prolongation of the micturition interval by CUR.
Collapse
Affiliation(s)
- Shohei Tobu
- Department of Urology, Saga University Faculty of Medicine, Saga, Japan
| | | | | | | | | |
Collapse
|
|
26
|
Zhang X, Shen F, Dong L, Zhao X, Qu X. Influence and pathophysiological mechanisms of simvastatin on prostatic hyperplasia in spontaneously hypertensive rats. Urol Int 2013; 91:467-73. [PMID: 23838355 DOI: 10.1159/000350519] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 03/06/2013] [Indexed: 11/19/2022]
Abstract
OBJECTIVE To explore the effects and mechanisms of simvastatin on prostate hyperplasia in spontaneously hypertensive rats (SHRs). METHODS Thirty-six male SHRs were randomly divided into three groups: the 10 and the 20 mg/kg/d simvastatin group and the control group. After 6 weeks the ultra-microscopic prostate structures were observed. The serum levels of interleukin-6 (IL-6), insulin-like growth factor (IGF-1) and angiotensin II (Ang-II) were measured by enzyme-linked immunosorbent assays. The endothelium-derived nitric oxide synthase (eNOS) expression was evaluated with immunohistochemistry. RESULTS Compared to the control group, the 20 mg/kg/d simvastatin group presented with lower absolute (p = 0.005) and relative prostate weight (p = 0.009). The basal cells and columnar cells presented with edema, condensed heterochromatin in interstitial fibroblast nuclei, widened nucleus gaps, and decreased mitochondria and endoplasmic reticulum in the 10 mg/kg/d simvastatin group, these changes were more pronounced in the 20 mg/kg/d simvastatin group. The IL-6 levels in the 10 and 20 mg/kg/d simvastatin groups were lower than those of the controls (p = 0.005 and p = 0.008). The IGF-1 levels of the 20 mg/kg/d simvastatin group were reduced compared to the control group (p = 0.016). CONCLUSIONS Simvastatin can delay and inhibit prostatic hyperplasia and progression in SHR. These actions may be mediated through the suppression of inflammatory and growth factors.
Collapse
Affiliation(s)
- Xiangyu Zhang
- Departments of Geriatrics and Urology, Second Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China
| | | | | | | | | |
Collapse
|
|
27
|
Domińska K, Piastowska-Ciesielska AW, Lachowicz-Ochędalska A, Ochędalski T. Similarities and differences between effects of angiotensin III and angiotensin II on human prostate cancer cell migration and proliferation. Peptides 2012; 37:200-6. [PMID: 22884921 DOI: 10.1016/j.peptides.2012.07.022] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 07/26/2012] [Accepted: 07/26/2012] [Indexed: 11/30/2022]
Abstract
Proliferation plays a critical role in tumor growth when cell migration is essential to invasion. The effect of Ang III and Ang II was evaluated on these important processes. Changes in the migration potential of prostate cancer cells were investigated using Wound Healing Test and a Transwell Migration Chamber with a 3 μm pore size. Cell proliferation was measured with a BrdU Assay and Countess Automated Cell Counter, thus determining the influence of angiotensins on hormone-dependent (LNCaP) and hormone-independent (DU-145) human prostate cancer lines. The influence of Ang III and Ang II on classic receptors may be inhibited by Losartan or PD123319. Test peptide modulation of the AT1 and AT2 receptors was examined by Western Blot and fluorescent immunocytochemistry. The results indicate that Ang III promotes the migration of both LNCaP and DU-145 lines, whereas Ang II stimulates this process only in androgen-independent cells. Both angiotensin peptides can induce prostate cancer cell proliferation in a time- and dose-dependent manner. The obtained results show that Ang III and Ang II can modify the expression of classic receptors, particularly AT2. These results suggest that the investigated peptide can modulate cell migration and proliferation in prostate cancer cells. Angiotensins probably have a greater influence on proliferation in the early-stage prostate cancer model than hormone-independent cell lines. Assume also that Ang II can enhance the migration tendency aggressive prostate cancer cells, while Ang III does so more effective in non-metastatic cells.
Collapse
Affiliation(s)
- Kamila Domińska
- Department of Comparative Endocrinology, Medical University of Lodz, Poland.
| | | | | | | |
Collapse
|
|
28
|
Tobu S, Noguchi M, Hatada T, Mori KI, Matsuo M, Sakai H. Changes in angiotensin II type 1 receptor expression in the rat bladder by bladder outlet obstruction. Urol Int 2012; 89:241-5. [PMID: 22777104 DOI: 10.1159/000339373] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 05/03/2012] [Indexed: 11/19/2022]
Abstract
PURPOSE To demonstrate the change in the expression of angiotensin II type 1 receptor (AT1) in the rat bladder with partial bladder outlet obstruction (P-BOO). MATERIALS AND METHODS Bladder specimens were obtained from 12-week-old Wistar female rats that were divided into two groups, a P-BOO group and a control group. The rats of the P-BOO group were divided into six groups: a sham-operated control group, 1 day postoperatively, 2 days postoperatively, 4 days postoperatively, 7 days postoperatively and 14 days postoperatively. The cystometric findings and immunohistochemical staining of the detrusor muscle with the AT1 antibody were compared in each group. RESULTS AT1 localized on the cell membrane of the detrusor smooth muscle and in cytoplasm of suburothelial myofibroblasts in the control rats. The expression of AT1 disappeared in the detrusor muscle and suburothelial myofibroblasts in P-BOO, but AT1 was highly expressed in urothelial cells 1 day after surgery. The expression of AT1 in urothelial cells gradually decreased with time after surgery. AT1 completely disappeared in urothelial cells 14 days after surgery. CONCLUSIONS The present study demonstrated that the site of AT1 expression changes in response to the mechanical stress caused by P-BOO, and finally there was no expression of AT1 in rat bladder tissue following P-BOO. These data suggest the change in AT1 expression may play a role in bladder function.
Collapse
Affiliation(s)
- Shohei Tobu
- Division of Nephro-Urology, Unit of Translational Medicine, Department of Medical and Dental Sciences, Nagasaki, Japan. toubu7 @ hotmail.com
| | | | | | | | | | | |
Collapse
|
|
29
|
Hasanzad M, Samzadeh M, Jamaldini SH, Haghdoost AA, Afshari M, Ziaei SAM. Association of Angiotensin I Converting Enzyme Polymorphism as Genetic Risk Factor in Benign Prostatic Hyperplasia and Prostate Cancer. Genet Test Mol Biomarkers 2012; 16:770-4. [DOI: 10.1089/gtmb.2011.0333] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
| | - Mohammad Samzadeh
- Urology and Nephrology Research Center (UNRC), Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Hamid Jamaldini
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Ali Akbar Haghdoost
- Research Center for Modeling of Health, Kerman University of Medical Sciences, Kerman, Iran
| | - Mahdi Afshari
- Research Center for Modeling of Health, Kerman University of Medical Sciences, Kerman, Iran
| | - Seyed Amir Mohsen Ziaei
- Urology and Nephrology Research Center (UNRC), Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
30
|
Ito H, Taga M, Tsuchiyama K, Akino H, Yokoyama O. IPSS is lower in hypertensive patients treated with angiotensin-II receptor blocker: posthoc analyses of a lower urinary tract symptoms population. Neurourol Urodyn 2012; 32:70-4. [PMID: 22693136 DOI: 10.1002/nau.22267] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2012] [Accepted: 04/11/2012] [Indexed: 12/20/2022]
Abstract
AIMS The existence of Angiotensin-II (Ang-II) receptors in the bladder wall and the pronounced contractile effect of Ang-II on the human detrusor muscle have been well established. Studies have presented the role of Ang-II as a mediator in smooth muscle growth and collagen production in the bladder with outlet obstruction. We investigated the associations between male lower urinary tract symptoms (LUTS) and hypertension (HT), and examined whether the medications used for HT treatment, particularly Ang-II receptor blockers (ARBs) influence LUTS. METHODS Among 4,298 men with LUTS who were nominated to participate in a Japanese study using the International Prostate Symptom Score (IPSS) to gain information on the effects and the safety of silodosin, a total of 3,790 men for whom a baseline IPSS was available were sub-analyzed. We analyzed the influence of HT treatment on IPSSs. RESULTS HT was the most common comorbidity (1,122 men, 29.6%), and 769 men (20.3%) were receiving some kinds of medication for the treatment. We found that the IPSS was lower in patients being treated for HT with ARB than in hypertensive patients who were not receiving any medication (16.8 ± 6.8 vs. 18.3 ± 6.6, P < 0.01). The baseline I-PSS in patients treated for HT with angiotensin converting enzyme inhibitor (ACE-I), calcium channel blocker (CCB), and normotensive patients were 18.3, 19.6, and 18.1, respectively. CONCLUSION The IPSS is lower in patients with HT treated with ARB. Other drugs for HT, including ACE-I and CCB, did not improve the IPSS.
Collapse
Affiliation(s)
- Hideaki Ito
- Department of Urology, Faculty of Medical Science, University of Fukui, Fukui, Japan.
| | | | | | | | | |
Collapse
|
|
31
|
Dominska K, Piastowska-Ciesielska AW, Pluciennik E, Lachowicz-Ochedalska A, Ochedalski T. A comparison of the effects of Angiotensin IV on androgen-dependent and androgen-independent prostate cancer cell lines. J Renin Angiotensin Aldosterone Syst 2012; 14:74-81. [PMID: 22679277 DOI: 10.1177/1470320312447649] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
INTRODUCTION Angiotensin IV is one of the biologically active peptides of the renin-angiotensin system. Limited data suggests that this hexapeptide could contribute to cancer development and/or progression. MATERIALS AND METHODS Using the MTT reduction assay as an indicator of cell viability, and the bromodeoxyuridine incorporation assay as an indicator of cell proliferation, the influence of Angiotensin IV was evaluated on two human prostate cancer lines: androgen-dependent (LNCaP) and androgen-independent (DU-145). The potential effect of Angiotensin IV classic angiotensin receptors was examined by using the selective antagonists losartan and PD123319. Finally, the changes in expression levels of AT1 and AT2 receptors were compared, before and after angiotensin treatment. RESULTS Angiotensin IV caused significant changes in cell viability and proliferation in LNCaP cells but not in DU-145. It was found that AT2 receptor blocker (PD123319) was able to diminish the suppressor effect of Angiotensin IV on bromodeoxyuridine incorporation into the DNA of androgen-dependent prostate cancer cells. Simultaneously, it was reported that Angiotensin IV is the factor that modulates the density of AT1 and AT2 receptors in prostate cancer cells. CONCLUSIONS These findings suggested that Angiotensin IV can modulate tumour cell proliferation in the early stage of androgen-dependent prostate cancer. The effect might be promoted by the change of the angiotensin receptor level.
Collapse
Affiliation(s)
- Kamila Dominska
- Department of Comparative Endocrinology, Medical University of Lodz, Poland.
| | | | | | | | | |
Collapse
|
|
32
|
Effect of AT1R knockdown on ishikawa cell proliferation induced by estrogen. Arch Gynecol Obstet 2012; 286:481-7. [PMID: 22484478 DOI: 10.1007/s00404-012-2305-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2011] [Accepted: 03/20/2012] [Indexed: 10/28/2022]
Abstract
OBJECTIVE This study aimed to study the effects of angiotensin receptor (AT1R) on proliferation, cell cycle progression, and apoptosis of estrogen-induced ishikawa cell by the transfection of AT1R-siRNA. METHODS Immunofluorescence method was used to detect AT1R in ishikawa cell. Western blot was used to detect the expression of AT1R protein in ishikawa cell before and after the transfection of AT1R-siRNA. MTT method was used to test the cell proliferation of estrogen-induced ishikawa cell before and after the transfection. Western blot was used to detect the expression of extracellular regulated protein kinase1/2(ERK1/2). RESULTS The result of immunofluorescence shows that AT1R was expressed in ishikawa cell. The expression of AT1R protein was inhibited obviously by 72 h after the transfection of AT1R-siRNA. The results of MTT show that estrogen could induce the cell proliferation of ishikawa cell. The expression of ERK1/2 was down-regulated after the transfection of AT1R-siRNA. CONCLUSION AT1R can promote the cell proliferation of estrogen-induced ishikawa cell. The possible mechanism may be down-regulating the expression of ERK1/2 protein.
Collapse
|
|
33
|
Yesudas R, Gumaste U, Snyder R, Thekkumkara T. Tannic acid down-regulates the angiotensin type 1 receptor through a MAPK-dependent mechanism. Mol Endocrinol 2012; 26:458-70. [PMID: 22322600 DOI: 10.1210/me.2011-1224] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
In the present study, we investigated the effects of tannic acid (TA), a hydrolysable polyphenol, on angiotensin type 1 receptor (AT1R) expression in continuously passaged rat liver epithelial cells. Under normal conditions, exposure of cells to TA resulted in the down-regulation of AT1R-specific binding in concentrations ranging from 12.5-100 μg/ml (7.34-58.78 μm) over a time period of 2-24 h with no change in receptor affinity to angiotensin II (AngII). The inhibitory effect of TA on AT1R was specific and reversible. In TA-treated cells, we observed a significant reduction in AngII-mediated intracellular calcium signaling, a finding consistent with receptor down-regulation. Under similar conditions, TA down-regulated AT1R mRNA expression without changing the rate of mRNA degradation, suggesting that TA's effect is mediated through transcriptional inhibition. Cells expressing recombinant AT1R without the native promoter show no change in receptor expression, whereas a pCAT reporter construct possessing the rat AT1R promoter was significantly reduced in activity. Furthermore, TA induced the phosphorylation of MAPK p42/p44. Pretreatment of the cells with a MAPK kinase (MEK)-specific inhibitor PD98059 prevented TA-induced MAPK phosphorylation and down-regulation of the AT1R. Moreover, there was no reduction in AngII-mediated intracellular calcium release upon MEK inhibition, suggesting that TA's observed inhibitory effect is mediated through MEK/MAPK signaling. Our findings demonstrate, for the first time, that TA inhibits AT1R gene expression and cellular response, suggesting the observed protective effects of dietary polyphenols on cardiovascular conditions may be, in part, through inhibition of AT1R expression.
Collapse
Affiliation(s)
- Rekha Yesudas
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, 1300 Coulter Drive, Amarillo, TX 79106, USA
| | | | | | | |
Collapse
|
|
34
|
Abstract
Much evidence now suggests that angiotensin II has roles in normal functions of the breast that may be altered or attenuated in cancer. Both angiotensin type 1 (AT1) and type 2 (AT2) receptors are present particularly in the secretory epithelium. Additionally, all the elements of a tissue renin-angiotensin system, angiotensinogen, prorenin and angiotensin-converting enzyme (ACE), are also present and distributed in different cell types in a manner suggesting a close relationship with sites of angiotensin II activity. These findings are consistent with the concept that stromal elements and myoepithelium are instrumental in maintaining normal epithelial structure and function. In disease, this system becomes disrupted, particularly in invasive carcinoma. Both AT1 and AT2 receptors are present in tumours and may be up-regulated in some. Experimentally, angiotensin II, acting via the AT1 receptor, increases tumour cell proliferation and angiogenesis, both these are inhibited by blocking its production or function. Epidemiological evidence on the effect of expression levels of ACE or the distribution of ACE or AT1 receptor variants in many types of cancer gives indirect support to these concepts. It is possible that there is a case for the therapeutic use of high doses of ACE inhibitors and AT1 receptor blockers in breast cancer, as there may be for AT2 receptor agonists, though this awaits full investigation. Attention is drawn to the possibility of blocking specific AT1-mediated intracellular signalling pathways, for example by AT1-directed antibodies, which exploit the possibility that the extracellular N-terminus of the AT1 receptor may have previously unsuspected signalling roles.
Collapse
Affiliation(s)
- Gavin P Vinson
- School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, UK.
| | | | | |
Collapse
|
|
35
|
Pawlikowski M, Minias R, Sosnowski M, Zieliński KW. Immunohistochemical detection of angiotensin AT 1 and AT 2 receptors in prostate cancer. Cent European J Urol 2011; 64:252-5. [PMID: 24578905 PMCID: PMC3921746 DOI: 10.5173/ceju.2011.04.art14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Revised: 07/28/2011] [Accepted: 08/08/2011] [Indexed: 12/17/2022] Open
Abstract
Introduction The human prostate gland contains all the compounds of the renin-angiotensin system (RAS), including AT1 and AT2 angiotensin receptors. The role of local RAS in the prostate pathology is recently discussed. The aim of the present study was the evaluation of AT1 and AT2 expressions in human prostate cancers. Material and methods The investigation was performed in 20 paraffin-embedded needle biopsy specimens from routine diagnostic prostate cancer biopsies. The specimens were stained with hematoxylin and eosin and immunostained with anti-AT1 and anti-AT2 antibodies. For visualization of primary antibodies, the streptavidin-biotin-peroxidase technique was applied. The expression of both receptor proteins was evaluated quantitatively using image analysis method. Results The positive immunostaining with both anti- AT1 and anti-AT2 antibodies can be found in stromal as well as epithelial structures. The results of quantitative evaluation showed the positive correlation between AT1 and AT2 expressions in neoplastic epithelium and overexpression of both AT1 and AT2 in neoplastic epithelium of Gleason grade 2, but not in cancerous structures of Gleason grades 3-5. Conclusions The data on AT1 and AT2 receptor expressions may suggest the involvement of RAS in prostate cancerogenesis. Moreover, the persistence of AT1 receptors in prostate cancer speaks in favor of attempts to use of AT1 receptor blockers (i.e. sartanes) and/or AT2 agonists in prostate cancer prophylaxis and/or treatment.
Collapse
Affiliation(s)
- Marek Pawlikowski
- Department of Neuroendocrinology, Chair of Endocrinology, Medical University of Łódź, Poland
| | - Radosław Minias
- Department of Clinical Pathomorphology and Cytopathology, Medical University of Łódź, Poland
| | | | - Krzysztof W Zieliński
- Department of Clinical Pathomorphology and Cytopathology, Medical University of Łódź, Poland
| |
Collapse
|
|
36
|
Uggere de Andrade T, Loiola LZ, Alcure SMN, Medeiros ARS, Santos MCLFS, Moysés MR, Abreu GRD, Lenz D, Bissoli NS. Role of the renin–angiotensin system in the nandrolone-decanoate-induced attenuation of the Bezold–Jarisch reflex. Can J Physiol Pharmacol 2011; 89:891-7. [DOI: 10.1139/y11-090] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The androgen nandrolone decanoate (ND) is known to cause cardiovascular abnormalities, such as attenuation of the Bezold–Jarisch Reflex (BJR), cardiac hypertrophy, and elevation of mean arterial pressure (MAP). Futhermore, a relationship between androgens and the renin–angiotensin system (RAS) has been reported. The purpose of this study was to evaluate the influence of RAS on the BJR, cardiac and prostatic hypertrophy, and MAP evoked by ND. For this, male Wistar rats were treated with ND (10 mg·(kg body mass)–1 for 8 weeks; DECA), or vehicle (control animals; CON), or enalapril (10 mg·(kg body mass)–1, daily; CONE), or ND and enalapril (10 mg ND + 10 mg enalapril per kilogram of body mass; DECAE). After 8 weeks of treatment, the BJR was evaluated by bradycardia and hypotensive responses that were elicited by serotonin administration (2–32 µg·(kg body mass)–1). MAP was assessed; cardiac and prostate hypertrophy were determined by the ratio of the tissue mass:body mass, and by histological analysis of the heart. Animals from the DECA group showed prostatic and cardiac hypertrophy, elevation in mean arterial pressure, and an impairment of BJR. Co-treatment with enalapril inhibited these changes. The data from the present study suggest that RAS has an impact on BJR attenuation, cardiac and prostatic hypertrophy, and the elevation in MAP evoked by ND.
Collapse
Affiliation(s)
| | - Leonardo Zanoteli Loiola
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espírito Santo, Avenida Marechal Campos, 1468, Vitória, ES 29042-755, Brazil
| | | | - Ana Raquel Santos Medeiros
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espírito Santo, Avenida Marechal Campos, 1468, Vitória, ES 29042-755, Brazil
| | | | - Margareth Ribeiro Moysés
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espírito Santo, Avenida Marechal Campos, 1468, Vitória, ES 29042-755, Brazil
| | - Gláucia Rodrigues de Abreu
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espírito Santo, Avenida Marechal Campos, 1468, Vitória, ES 29042-755, Brazil
| | - Dominik Lenz
- Department of Pharmacy, University Center of Vila Velha, Espírito Santo, Brazil
| | - Nazaré Souza Bissoli
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espírito Santo, Avenida Marechal Campos, 1468, Vitória, ES 29042-755, Brazil
| |
Collapse
|
|
37
|
Bid HK, Manchanda PK, Konwar R, Hanif K, Nayak VL, Singh V. Does angiotensin-converting enzyme polymorphism have association with symptomatic benign prostatic hyperplasia? Indian J Urol 2011; 26:497-501. [PMID: 21369379 PMCID: PMC3034055 DOI: 10.4103/0970-1591.74438] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Objectives: The aim of the study was to explore the putative significance of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and its correlation with the lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia (BPH). Materials and Methods: ACE I/D polymorphisms were determined by polymerase chain reaction (PCR) in 200 patients with moderate to severe LUTS due to BPH and 200 patients of same age group without the LUTS having normal size prostate. ACE levels were estimated by spectrophotometer method. Logistic regression models were used to determine the genetic effects using SPSS statistical software (version 12.0). Results and Conclusions: The distribution of genotypes along with allelic frequency and carriage rate did not significantly differ between study and control groups. This study suggests that I/D polymorphisms within the ACE gene are not associated with the presence of LUTS in BPH patients. Future studies in large cohorts are needed that may reveal the spectrum of cellular mechanism mediated by ACE relevant to pathophysiology of BPH and effect of ethnic differences.
Collapse
Affiliation(s)
- Hemant Kumar Bid
- Endocrinology Division, Central Drug Research Institute, Lucknow-226 001, India
| | | | | | | | | | | |
Collapse
|
|
38
|
Louis SN, Chow L, Rezmann L, Krezel MA, Catt KJ, Tikellis C, Frauman AG, Louis WJ. Expression and function of ATIP/MTUS1 in human prostate cancer cell lines. Prostate 2010; 70:1563-74. [PMID: 20687230 PMCID: PMC6528809 DOI: 10.1002/pros.21192] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND We have previously demonstrated Ang II type 2 (AT(2)-) receptor-mediated inhibition of EGF-induced prostate cancer cell growth in androgen-dependent (LNCaP) and independent (PC3) prostate cancer cell lines. METHODS To explore the signaling pathways involved in this inhibitory effect, we examined the interaction of the AT(2)-receptor with its novel regulatory partner ATIP using real time PCR, over-expression, siRNA and [(3)H]thymidine incorporation assays. RESULTS The results in human prostate cancer cell lines demonstrate the presence of ATIP in both cell lines examined, and suggest that (i) the AT(2)-receptor through an interaction with ATIP mediates an anti-growth factor effect in both androgen-dependent and androgen-independent cell lines; (ii) ATIP expression decreases as the rate of cell growth and androgen-independence increase; and (iii) EGF may act on cell growth in part by reducing the content of ATIP present in the cells. CONCLUSIONS The results support our earlier proposal in normal cell lines that ATIP is an important component of the cellular response to AT(2)-receptor activation. The results further suggest that a critical level of ATIP is required to mediate the effect of AT(2)-receptor activation to inhibit EGF mediated increases in cell growth. They also suggest that EGF may in part induce cell growth by suppressing the level of ATIP expression.
Collapse
Affiliation(s)
- Simon N.S. Louis
- Clinical Pharmacology and Therapeutics Unit, University of Melbourne, Department of Medicine, Austin Health, Heidelberg, Victoria, Australia
| | - Laurie Chow
- Clinical Pharmacology and Therapeutics Unit, University of Melbourne, Department of Medicine, Austin Health, Heidelberg, Victoria, Australia
| | - Linda Rezmann
- Clinical Pharmacology and Therapeutics Unit, University of Melbourne, Department of Medicine, Austin Health, Heidelberg, Victoria, Australia
| | - Michael A. Krezel
- Clinical Pharmacology and Therapeutics Unit, University of Melbourne, Department of Medicine, Austin Health, Heidelberg, Victoria, Australia
| | - Kevin J. Catt
- Section on Hormonal Regulation, PEDGEN, NICHD, National Institutes of Health, Bethesda, Maryland
| | - Chris Tikellis
- Baker Heart Research Institute, Melbourne, Victoria, Australia
| | - Albert G. Frauman
- Clinical Pharmacology and Therapeutics Unit, University of Melbourne, Department of Medicine, Austin Health, Heidelberg, Victoria, Australia
| | - William J. Louis
- Clinical Pharmacology and Therapeutics Unit, University of Melbourne, Department of Medicine, Austin Health, Heidelberg, Victoria, Australia
| |
Collapse
|
|
39
|
Zhao Y, Peng J, Zheng L, Yu W, Jin J. Transforming growth factor beta1 mediates apoptotic activity of angiotensin II type I receptor blocker on prostate epithelium in vitro. Prostate 2010; 70:899-905. [PMID: 20135646 DOI: 10.1002/pros.21124] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND The significant association of benign prostatic hyperplasia (BPH) and hypertension indicates a common pathophysiological factor for both diseases. Hyperactivity of the renin-angiotensin system (RAS) has been reported in BPH. Angiotensin II type I (AT1) receptor is the principal mediator of the RAS, and the antagonist, AT1 receptor blocker (ARB), can induce apoptosis in prostate epithelium cells and increase transforming growth factor beta1 (TGF-beta1) expression. We aimed to investigate the mechanism of inhibition of AT1 receptor in prostate epithelium cells and the role of TGF-beta1. METHODS Human prostate epithelium cell lines were treated with different concentrations of ARB (losartan) (0, 0.1, 1, 10, 100, and 1,000 microM) for 24-72 hr. Cell proliferation was analyzed by cell proliferation assay. The location of AT1 receptor was shown by immunocytohistochemistry and immunocytofluorescence study. Analysis of apoptosis was by use of terminal transferase TdT-mediated dUTP-biotin end labeling (TUNEL) and caspase 3/7 activity assay. Mitochondrial outer-membrane permeabilization was measured by JC-1 staining. The level of TGF-beta1 was determined by enzyme-linked immunosorbent assay. RESULTS Immunohistochemistry and immunofluorescence analysis showed AT1 receptor expressed in epithelium cells. Compared to control cultures, cultures treated with losartan for 24-72 hr showed a dose-dependent significant decrease in cell number, with apoptosis increased by 65.2%. Decreased cell number was reversed on treatment with anti-TGF-beta1 antibody. TUNEL staining showed increased apoptosis in prostate epithelium cells exposed to losartan. Caspase 3/7 activation was increased and mitochondrial membrane potential was downregulated. Expression of TGF-beta1 in cells treated with losartan was higher than that in untreated cells. CONCLUSIONS The apoptotic effect of blockade of AT1 receptor on human prostatic epithelium cells may be mediated through an autocrine the production of TGF-beta1. Furthermore, this finding may have implications for medication options. Inc.
Collapse
Affiliation(s)
- Yayuan Zhao
- Department of Urology, Peking University First Hospital, Beijing, China.
| | | | | | | | | |
Collapse
|
|
40
|
Li H, Qi Y, Li C, Braseth LN, Gao Y, Shabashvili AE, Katovich MJ, Sumners C. Angiotensin type 2 receptor–mediated apoptosis of human prostate cancer cells. Mol Cancer Ther 2009; 8:3255-65. [DOI: 10.1158/1535-7163.mct-09-0237] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
|
|
41
|
|
|
42
|
Chow L, Rezmann L, Catt KJ, Louis WJ, Frauman AG, Nahmias C, Louis SNS. Role of the renin-angiotensin system in prostate cancer. Mol Cell Endocrinol 2009; 302:219-29. [PMID: 18824067 DOI: 10.1016/j.mce.2008.08.032] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2008] [Revised: 08/29/2008] [Accepted: 08/29/2008] [Indexed: 11/19/2022]
Abstract
Prostate cancer is highly prevalent in Western society, and its early stages can be controlled by androgen ablation therapy. However, the cancer eventually regresses to an androgen-independent state for which there is no effective treatment. The renin-angiotensin system (RAS), in particular the octapeptide angiotensin II, is now recognised to have important effects on growth factor signalling and cell growth in addition to its well known actions on blood pressure, fluid homeostasis and electrolyte balance. All components of the RAS have been recently identified in the prostate, consistent with the expression of a local RAS system in this tissue. This review focuses on the role of the RAS in the prostate, and the possibility that this pathway may be a potential therapeutic target for the treatment of prostate cancer and other prostatic diseases.
Collapse
Affiliation(s)
- L Chow
- University of Melbourne, Department of Medicine, Austin Health, Heidelberg, Victoria, Australia
| | | | | | | | | | | | | |
Collapse
|
|
43
|
Chow L, Rezmann L, Imamura K, Wang L, Catt K, Tikellis C, Louis WJ, Frauman AG, Louis SNS. Functional angiotensin II type 2 receptors inhibit growth factor signaling in LNCaP and PC3 prostate cancer cell lines. Prostate 2008; 68:651-60. [PMID: 18288685 DOI: 10.1002/pros.20738] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND There is clear evidence of a tissue-based renin-angiotensin system in the prostate and studies to date suggest that AT(1)-receptor blocking drugs inhibit the growth of some prostate cancer cell lines and delay the development of prostate cancer. The present studies examine the action of Ang II in two prostate cancer cell lines and report the presence of functional AT(2)-receptors that regulate the actions of growth factors. METHODS Immunohistochemistry was used to identify the presence of Ang II and QPCR techniques to examine AT(1)- and AT(2)-receptor mRNA expression in androgen-dependent (LNCaP) and independent (PC3) cell lines. The effects of AT(1)- and AT(2)-receptor activation upon EGF-induced DNA synthesis and ERK2 phosphorylation in these cells were also examined. RESULTS Functional AT(2)-receptors together with Ang II were identified in both cell lines and stimulation of these receptors inhibited EGF-induced DNA synthesis and ERK2 phosphorylation. AT(1)-receptors, although present in both cell lines, were only functional in LNCaP cells where activation stimulated DNA synthesis. CONCLUSIONS Functional AT(2)-receptors are present and have the capacity to inhibit EGF-induced prostate cancer cell growth in LNCaP and fast growing androgen-independent PC3 cell lines, whereas functional AT(1)-receptors are found only in LNCaP cells where their activation stimulates DNA synthesis.
Collapse
MESH Headings
- Cell Line, Tumor
- DNA/biosynthesis
- DNA/drug effects
- Epidermal Growth Factor/metabolism
- Gene Expression Regulation, Neoplastic/drug effects
- Gene Expression Regulation, Neoplastic/physiology
- Humans
- Male
- Mitogen-Activated Protein Kinase 1/metabolism
- Phosphorylation
- Prostatic Neoplasms/genetics
- Prostatic Neoplasms/metabolism
- Prostatic Neoplasms/pathology
- RNA, Messenger/metabolism
- RNA, Neoplasm/analysis
- Receptor, Angiotensin, Type 1/genetics
- Receptor, Angiotensin, Type 1/metabolism
- Receptor, Angiotensin, Type 2/physiology
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction/drug effects
- Signal Transduction/physiology
Collapse
Affiliation(s)
- L Chow
- Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
| | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Angiotensin II type 1 receptor antagonist suppress angiogenesis and growth of gastric cancer xenografts. Dig Dis Sci 2008; 53:1206-10. [PMID: 17934850 DOI: 10.1007/s10620-007-0009-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2007] [Accepted: 08/28/2007] [Indexed: 12/14/2022]
Abstract
Angiotensin II (Ang II) has been reported to promote tumor progression, tumor growth and angiogenesis in many cancers. We previously observed that angiotensin II type 1 receptors (AT1R) were upregulated in human gastric cancer and may be involved in the progression of gastric cancer. We studied the effects of AT1R antagonist on angiogenesis and growth in gastric cancer xenografts to observe the mechanism action of AT1R in the gastric cancer. The results showed that the growth of gastric cancer cells was significantly suppressed by treatment with AT1R antagonist. In vivo, TCV-116, at doses of both 2 and 5 mg/kg/day, significantly suppressed tumor growth in mice (47.3 and 70.2%). Microvessel density was significantly decreased by TCV-116 (3.4 +/- 0.9 and 2.8 +/- 0.5 per field) compared with the control group (12.9 +/- 1.1 per field), and VEGF expression was significantly suppressed by AT1R antagonist. These results demonstrate that AT1R plays an important role in the progression of gastric cancer. Suppression tumor angiogenesis could be one of the mechanisms by which AT1R antagonist suppresses the growth of gastric cancer. These findings also provide a theoretical basis for the future clinical application of AT1R antagonist against gastric cancer.
Collapse
|
|
45
|
Uemura H, Ishiguro H, Ishiguro Y, Hoshino K, Takahashi S, Kubota Y. Angiotensin II induces oxidative stress in prostate cancer. Mol Cancer Res 2008; 6:250-8. [PMID: 18314486 DOI: 10.1158/1541-7786.mcr-07-0289] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Angiotensin II has been shown to be a cytokine especially acting as a growth factor. A local renin-angiotensin system has been identified in the prostate gland, and the physiologic function of angiotensin II seems to be similar in prostate cancer, as we previously reported. In the present study, we explored the biological role of angiotensin II in oxidative stress of prostate cancer cells. Activated Akt was determined, and the expression of oxidative stress-related proteins (p47phox, manganese superoxide dismutase 2, glutathione peroxidase) was examined by Western blotting in LNCaP cells, which were stimulated with angiotensin II and/or an angiotensin II receptor type 1 blocker, candesartan. To examine DNA damage induced by angiotensin II, 8-hydroxy-2'-deoxyguanosine was determined, and Western blots were analyzed to detect checkpoint proteins including p53, Chk2, and cdc2. Immunocytochemical studies of inducible nitric oxide synthase and superoxide anion radical (O(2)(-)) were done in LNCaP cells stimulated with angiotensin II. The phosphorylation of Akt was induced by angiotensin II treatment and inhibited by candesartan, as well as by LY294002, an inhibitor of phosphoinositide 3-kinase. Oxidative stress-related proteins were up-regulated by angiotensin II and inhibited by pretreatment with candesartan or catalase. The level of 8-hydroxy-2'-deoxyguanosine was increased by angiotensin II and conversely decreased by candesartan. Immunocytochemical studies showed that angiotensin II enhanced an inflammatory marker, inducible nitric oxide synthase, and the production of O(2)(-) radical. The hypothesis that angiotensin II has the potential to induce oxidative stress, which may be implicated in carcinogenesis of the prostate gland through long-term exposure to chronic inflammation is proposed.
Collapse
Affiliation(s)
- Hiroji Uemura
- Department of Urology, Yokohama City University School of Medicine, Yokohama, Japan.
| | | | | | | | | | | |
Collapse
|
|
46
|
Huang W, Yu LF, Zhong J, Qiao MM, Jiang FX, Du F, Tian XL, Wu YL. Angiotensin II type 1 receptor expression in human gastric cancer and induces MMP2 and MMP9 expression in MKN-28 cells. Dig Dis Sci 2008; 53:163-8. [PMID: 17486447 DOI: 10.1007/s10620-007-9838-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2006] [Accepted: 03/30/2007] [Indexed: 12/09/2022]
Abstract
Angiotensin II (Ang II), a main effector peptide in the renin-angiotensin system, acts as a growth-promoting and angiogenic factor via angiotensin II receptor1 (AT1R). In this study, we investigated the expression of angiotensin II type1 receptor (AT1R) in gastric cancer and the effects of Ang II on the expression of MMP2 and MMP9 in the human gastric cancer cell line MKN-28 cells. The expression of the Ang II type I receptor was examined by western and immunocytochemistry in gastric cancer cell lines and detected by real-time PCR and immunohistochemistry in normal and gastric cancer tissues. The expression of MMP2 and MMP9 were detected by real-time PCR and western after treatment with Ang II and/or AT1R antagonist. AT1R were expressed in all human gastric cancer lines and the expression of AT1R was significantly higher in cancer tissues than that in normal gastric tissues (P < 0.01). Furthermore, Ang II promoted the expression of MMP2 and MMP9 in MKN-28 cells, and the stimulatory effects of Ang II could be blocked by AT1R antagonist. These results suggest that AT1R is involved in the progression of gastric cancer and may promote the angiogenesis of gastric cancer cell line (MKN-28), and these effects may be associated with the upregulation of MMP2 and MMP9.
Collapse
MESH Headings
- Biomarkers, Tumor/biosynthesis
- Biomarkers, Tumor/genetics
- Blotting, Western
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic
- Humans
- Immunohistochemistry
- Matrix Metalloproteinase 2/biosynthesis
- Matrix Metalloproteinase 2/genetics
- Matrix Metalloproteinase 9/biosynthesis
- Matrix Metalloproteinase 9/genetics
- RNA, Neoplasm/genetics
- Receptor, Angiotensin, Type 1/biosynthesis
- Receptor, Angiotensin, Type 1/genetics
- Reverse Transcriptase Polymerase Chain Reaction
- Stomach Neoplasms/genetics
- Stomach Neoplasms/metabolism
- Stomach Neoplasms/pathology
- Up-Regulation/genetics
Collapse
Affiliation(s)
- Wei Huang
- Department of Gastroenterology, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai, China
| | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Louis SN, Wang L, Chow L, Rezmann LA, Imamura K, MacGregor DP, Casely D, Catt KJ, Frauman AG, Louis WJ. Appearance of angiotensin II expression in non-basal epithelial cells is an early feature of malignant change in human prostate. ACTA ACUST UNITED AC 2007; 31:391-5. [PMID: 18031950 DOI: 10.1016/j.cdp.2007.08.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2007] [Indexed: 11/18/2022]
Abstract
BACKGROUND Despite increasing interest in the renin-angiotensin system in cancer, little is known about angiotensin II (Ang II) expression in human prostate tumors. METHODS Using immunohistochemistry, we examined Ang II expression in prostate cancer (Gleason grades 2-5), benign prostatic hyperplasia (BPH), and high-grade prostatic intraepithelial neoplasia (HGPIN). RESULTS Ang II was present in proliferating neoplastic cells in HGPIN, in malignant cells in all grades of prostate cancer examined, in basal but not luminal epithelial cells in BPH, and in the cytoplasm of LNCaP, DU145, and PC3 prostate cancer cells. CONCLUSIONS The data establishes the presence of Ang II in pre-malignant and malignant prostate cells, suggests Ang II staining in non-basal epithelial cells is an early sign of malignant change, and supports suggestions that HGPIN and malignant prostate cells both arise from transformed basal cells. Using immunohistochemistry we examined Ang II expression in proliferative disorders of the prostate and concluded that Ang II staining in non-basal epithelial cells is evidence of early malignant change.
Collapse
Affiliation(s)
- Simon N Louis
- Clinical Pharmacology and Therapeutics Unit, University of Melbourne, Department of Medicine, Austin Health, Heidelberg, 3084 Vic., Australia
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Yu W, Zhao YY, Zhang ZW, Guo YL, Jin J. Angiotension II receptor 1 blocker modifies the expression of apoptosis-related proteins and transforming growth factor-beta1 in prostate tissue of spontaneously hypertensive rats. BJU Int 2007; 100:1161-5. [PMID: 17784886 DOI: 10.1111/j.1464-410x.2007.07150.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE To assess whether angiotensin II (Ang II), important in hypertension and highly expressed in benign prostatic hyperplasia (BPH), is involved in prostate growth, by analysing changes in the histological composition, tissue apoptotic status and level of transforming growth factor-beta1 (TGFbeta1) induced by an Ang II type 1 receptor blocker, losartan, in the prostates of spontaneously hypertensive (SH) rats. MATERIALS AND METHODS We assessed four groups of six rats each: normotensive Wistar-Kyoto counterparts of SH rats; untreated SH rats; SH rats given low-dose losartan (10 mg/kg/day for 10 weeks); and SH given high-dose losartan (30 mg/kg/day for 10 weeks). We evaluated the histological composition and expression of TGFbeta1 and apoptosis-related proteins, i.e. Bax and the 116-kDa poly (adenosine diphosphate-ribose) polymerase (PARP), by Western blotting in the rat prostate ventral lobes. RESULTS Compared with Wistar-Kyoto rats, untreated SH rats had a significantly increased epithelium component in the prostate (P < 0.01), but with losartan treatment, SH rats showed less of the epithelium component than untreated rats (P < 0.01 for both low- and high-dose losartan). Western-blot analysis showed a significantly increased level of Bax in high-dose losartan-treated rats (P < 0.01). The expression of 116 kDa PARP was also decreased in these rats (P < 0.01), which suggests increased caspase-3 activity. In addition, TGFbeta1 levels were significantly elevated in high-dose losartan-treated rats (P < 0.01). CONCLUSION These results show that losartan can induce apoptosis of prostate epithelium and increase the TGFbeta1 expression in SH rats, suggesting that Ang II stimulation might be involved in the pathogenesis of BPH, which might correlate with the regulation of TGFbeta1 expression.
Collapse
Affiliation(s)
- Wei Yu
- Department of Urology, Peking University First Hospital, Peking University, and Department of Physiology and Pathophysiology, Peking University, China
| | | | | | | | | |
Collapse
|
|
49
|
|
|
50
|
Abstract
Lower urinary tract symptoms (LUTS) are commonly divided into storage, voiding, and postmicturition symptoms, and may occur in both men and women. Male LUTS have historically been linked to benign prostatic hyperplasia (BPH), but are not necessarily prostate related. The focus of treatment for LUTS has thus shifted from the prostate to the bladder and other extraprostatic sites. LUTS include symptoms of the overactive bladder (OAB), which are often associated with detrusor overactivity. Treatment for LUTS suggestive of BPH has traditionally involved the use of alpha(1)-adrenoceptor (AR) antagonists; 5alpha-reductase inhibitors; and phytotherapy-however, several new therapeutic principles have shown promise. Selective beta(3)-adrenoceptor agonists and antimuscarinics are potentially useful agents for treating LUTS, particularly for storage symptoms secondary to outflow obstruction. Other agents of potential or actual importance are antagonists of P2X(3) receptors, botulinum toxin type A, endothelin (ET)-converting enzyme inhibitors, and drugs acting at vanilloid, angiotensin, and vitamin D(3) receptor sites. Drugs interfering with the nitric oxide/cGMP-cAMP pathway, Rho-kinase and COX inhibitors, as well as drugs targeting receptors and mechanisms within the CNS, are also of interest and deserving of further study for the treatment of LUTS.
Collapse
Affiliation(s)
- K-E Andersson
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157, USA.
| |
Collapse
|