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Martinez P, Grant WB. Vitamin D: What role in obesity-related cancer? Semin Cancer Biol 2025; 112:135-149. [PMID: 40194750 DOI: 10.1016/j.semcancer.2025.03.007] [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: 12/06/2024] [Revised: 03/16/2025] [Accepted: 03/29/2025] [Indexed: 04/09/2025]
Abstract
Obesity is an important risk factor for incidence and death for many types of cancer. Vitamin D reduces risk of incidence and death for many types of cancer. This review outlines the mechanisms by which obesity increases risk of cancer, how vitamin D reduces risk of cancer, and the extent to which vitamin D counters the effects of obesity in cancer. Vitamin D is a partial ally against some of obesity's pro-carcinogenic effects, notably by reducing inflammation and regulating sex hormone receptors, leptin resistance, cellular energy metabolism, the microbiome, and hypoxia. However, it can act stronger in against the renin-angiotensin system, insulin resistance, and oxidative stress in cancer. Additionally, excess fat tissue sequesters vitamin D and, along with its dilution in increased body volume, further reduces its bioavailability and serum concentration, limiting its protective effects against cancer. In conclusion, while vitamin D cannot reverse obesity, it plays a significant role in mitigating its pro-carcinogenic effects by targeting several mechanisms.
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Affiliation(s)
| | - William B Grant
- Sunlight, Nutrition, and Health Research Center, 1745 Pacific Ave., Ste. 504, San Francisco, CA 94109, USA.
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2
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Gintoni I, Mastrogeorgiou M, Papakosta V, Vassiliou S, Yapijakis C. Genetic Variations Related to Angiotensin II Production and Risk for Basal Cell Carcinoma. Biochem Genet 2025; 63:917-935. [PMID: 38546913 DOI: 10.1007/s10528-024-10746-0] [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: 05/30/2023] [Accepted: 02/16/2024] [Indexed: 03/23/2025]
Abstract
Basal cell carcinoma (BCC) is the most prevalent human neoplasm, with constantly increasing annual incidence. Despite its slow growth, BCC is locally invasive and, if left untreated, can cause severe complications, including metastasis and death. The renin-angiotensin system (RAS) plays a key role in electrolyte balance, atrial pressure, tissue development, homeostasis, and inflammation, but also in cancer development. After binding to its type 1 receptor (AT1R), angiotensin II (ANGII), the system's principal hormonal effector, regulates cancer pathways spanning from the formation of the initial cancer cell to the construction and nutrition of the tumor microenvironment, angiogenesis, proliferation, and metastasis. Although the role of RAS in the development of skin pathologies has not been widely researched, RAS-targeting antihypertensive medications have been shown to have a chemoprotective effect against BCC. Based on those findings, our group conducted a series of genetic association studies to investigate the association between common functional variations in key genes related to ANGII production (AGT, ACE, ACE2, AT1R, AT2R, and CMA1) and the risk of BCC occurrence. This review provides a summary of the current understanding of the ANGII involvement in BCC development. The reliable and easily assessed pool of genetic biomarkers may be used for predictive testing and prevention purposes in high-risk individuals.
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Affiliation(s)
- Iphigenia Gintoni
- Unit of Orofacial Genetics, 1st Department of Pediatrics, National Kapodistrian University of Athens, University Research Institute for the Study of Genetic and Malignant Disorders in Childhood, Choremion Laboratory "Hagia Sophia" Children's Hospital, Athens, Greece
- Department of Molecular Genetics, Cephalogenetics Center, Philaretou 88, Kallithea, 17675, Athens, Greece
- Department of Oral and Maxillofacial Surgery, School of Medicine, National and Kapodistrian University of Athens, Attikon Hospital, Athens, Greece
| | - Michael Mastrogeorgiou
- Unit of Orofacial Genetics, 1st Department of Pediatrics, National Kapodistrian University of Athens, University Research Institute for the Study of Genetic and Malignant Disorders in Childhood, Choremion Laboratory "Hagia Sophia" Children's Hospital, Athens, Greece
| | - Veronica Papakosta
- Department of Oral and Maxillofacial Surgery, School of Medicine, National and Kapodistrian University of Athens, Attikon Hospital, Athens, Greece
| | - Stavros Vassiliou
- Department of Oral and Maxillofacial Surgery, School of Medicine, National and Kapodistrian University of Athens, Attikon Hospital, Athens, Greece
| | - Christos Yapijakis
- Unit of Orofacial Genetics, 1st Department of Pediatrics, National Kapodistrian University of Athens, University Research Institute for the Study of Genetic and Malignant Disorders in Childhood, Choremion Laboratory "Hagia Sophia" Children's Hospital, Athens, Greece.
- Department of Molecular Genetics, Cephalogenetics Center, Philaretou 88, Kallithea, 17675, Athens, Greece.
- Department of Oral and Maxillofacial Surgery, School of Medicine, National and Kapodistrian University of Athens, Attikon Hospital, Athens, Greece.
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Chang Q, Zhao S, Sun J, Guo W, Yang L, Qiu L, Zhang N, Fan Y, Liu J. Identification of a novel prognostic and therapeutic prediction model in clear cell renal carcinoma based on Renin-angiotensin system related genes. Front Endocrinol (Lausanne) 2025; 16:1521940. [PMID: 40099255 PMCID: PMC11911175 DOI: 10.3389/fendo.2025.1521940] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 02/11/2025] [Indexed: 03/19/2025] Open
Abstract
Background Clear cell renal cell carcinoma is the most predominant type of renal malignancies, characterized by high aggressiveness and probability of distant metastasis. Renin angiotensin system (RAS) plays a crucial role in maintaining fluid balance within the human body, and its involvement in tumorigenesis is increasingly being uncovered, while its role in ccRCC remains unclear. Methods WGCNA was used to identify RAS related genes. Machine learning was applied to screen hub genes for constructing risk model, E-MTAB-1980 dataset was used for external validation. Transwell and CCK8 assays were used to investigate the impact of SLC6A19 to ccRCC cells. Results SLC6A19, SLC16A12 and SMIM24 were eventually screened to construct risk model and the predictive efficiency for prognosis was validated by internal and external cohorts. Moreover, the differences were found in pathway enrichment, immune cell infiltration, mutational landscapes and drug prediction between high and low risk groups. Experimental results indicated that SLC6A19 could inhibit invasion and proliferation of ccRCC cells and GSEA pinpointed that SLC6A19 was intimately correlated with fatty acid metabolism and CPT1A. Conclusion The risk model based on the three RAS-related genes have a robust ability to predict the prognosis and drug sensitivity of ccRCC patients, further providing a valid instruction for clinical care.
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Affiliation(s)
| | | | | | | | | | | | | | - Yidong Fan
- Department of Urology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Jikai Liu
- Department of Urology, Qilu Hospital of Shandong University, Jinan, Shandong, China
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Andersen MD, Wolter K, Enemark MBH, Pedersen MA, Gormsen LC, Lauridsen KL, Starklint J, Hamilton‐Dutoit SJ, d'Amore F, Ludvigsen M, Honoré B, Kamper P. Proteomic Profiling of Lymph Nodes Differentiates Classic Hodgkin Lymphoma With and Without Skeletal Involvement. Eur J Haematol 2025; 114:173-185. [PMID: 39394762 PMCID: PMC11613579 DOI: 10.1111/ejh.14326] [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: 07/08/2024] [Revised: 09/26/2024] [Accepted: 09/30/2024] [Indexed: 10/14/2024]
Abstract
Classic Hodgkin lymphoma (CHL) is a highly curable disease, even in advanced stages. Controversy remains over whether bone involvement negatively affects overall and progression-free survival in patients treated with intensive chemotherapy regimens. Whether cases that present with bone lesions harbor specific tumor microenvironmental features is unknown. We investigated protein expression in diagnostic lymph node biopsies from CHL patients with and without skeletal involvement at diagnosis to identify potential markers of skeletal disease. Protein expression patterns in diagnostic formalin-fixed paraffin-embedded lymphoma lymph node samples from CHL patients were analyzed by nano-liquid chromatography-tandem mass spectrometry. Patients were grouped according to skeletal involvement, which was defined as the presence of one or more FDG-avid lesions on a diagnostic FDG-PET/CT scan. Protein profiles identified patients with skeletal disease at diagnosis and showed disrupted cellular pathways, including immune system processes, cell adhesion, and cell growth/survival. Immunohistochemical evaluation also demonstrated differential expressions of angiotensin-converting enzyme (ACE), intercellular adhesion molecule 3 (ICAM3), integrin alpha-X (ITGAX), and calreticulin (CALR). In conclusion, proteomics identified altered protein expression profiles in lymph nodes among CHL cases presenting with disease disseminated to the skeletal system, which implies altered disease pathogenesis for these patients.
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Affiliation(s)
- Maja Dam Andersen
- Department of HaematologyAarhus University HospitalAarhusDenmark
- Department of Clinical MedicineAarhus UniversityAarhusDenmark
| | - Katharina Wolter
- Department of HaematologyAarhus University HospitalAarhusDenmark
| | - Marie Beck Hairing Enemark
- Department of HaematologyAarhus University HospitalAarhusDenmark
- Department of Clinical MedicineAarhus UniversityAarhusDenmark
| | - Mette Abildgaard Pedersen
- Department of BiomedicineAarhus UniversityAarhusDenmark
- Department of Nuclear Medicine & PET CentreAarhus University HospitalAarhusDenmark
| | | | | | - Jørn Starklint
- Department of MedicineRegional Hospital GoedstrupHerningDenmark
| | | | - Francesco d'Amore
- Department of HaematologyAarhus University HospitalAarhusDenmark
- Department of Clinical MedicineAarhus UniversityAarhusDenmark
| | - Maja Ludvigsen
- Department of HaematologyAarhus University HospitalAarhusDenmark
- Department of Clinical MedicineAarhus UniversityAarhusDenmark
| | - Bent Honoré
- Department of BiomedicineAarhus UniversityAarhusDenmark
| | - Peter Kamper
- Department of HaematologyAarhus University HospitalAarhusDenmark
- Department of Clinical MedicineAarhus UniversityAarhusDenmark
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Yoon SY, Oh J. Cardiovascular Autonomic Dysfunction Before and After Chemotherapy in Cancer Patients. J Clin Neurol 2024; 20:551-562. [PMID: 39505307 PMCID: PMC11543394 DOI: 10.3988/jcn.2024.0221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 09/20/2024] [Accepted: 09/23/2024] [Indexed: 11/08/2024] Open
Abstract
Complications that occur during cancer therapy have emerged as a major contributor to the poor quality of life experienced by cancer patients as they live longer due to improved treatments. Many studies have investigated chemotherapy-induced peripheral neuropathy, but few have investigated the autonomic nervous system. Cardiovascular autonomic dysfunction (CAD) contributes to the distressing symptoms experienced by cancer patients, and it is also related to poor treatment outcomes. CAD has a multifactorial etiology in patients with cancer: it can be caused by the cancer itself, chemotherapy or radiation therapy, or other comorbidities. Its symptoms are nonspecific, and they include orthostatic hypotension, resting tachycardia, dizziness, chest tightness, and exertional dyspnea. It is important to suspect CAD and perform therapeutic interventions in a clinical context, because a patient who is more frail is less like to endure the treatment process. The quality of life of patients receiving active cancer treatments can be improved by evaluating the risk of CAD before and after chemotherapy, and combining both nonpharmacological and pharmacological management. Here we review the prevalence, pathogenesis, diagnosis, and treatment of CAD, which is the most common and a sometimes serious symptom in cancer patients.
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Affiliation(s)
- So Young Yoon
- Department of Oncology, Konkuk University Medical Center, Seoul, Korea
| | - Jeeyoung Oh
- Department of Neurology, Konkuk University Medical Center, Seoul, Korea.
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Bernstein KE, Cao D, Shibata T, Saito S, Bernstein EA, Nishi E, Yamashita M, Tourtellotte WG, Zhao TV, Khan Z. Classical and nonclassical effects of angiotensin-converting enzyme: How increased ACE enhances myeloid immune function. J Biol Chem 2024; 300:107388. [PMID: 38763333 PMCID: PMC11208953 DOI: 10.1016/j.jbc.2024.107388] [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: 02/26/2024] [Revised: 05/01/2024] [Accepted: 05/07/2024] [Indexed: 05/21/2024] Open
Abstract
As part of the classical renin-angiotensin system, the peptidase angiotensin-converting enzyme (ACE) makes angiotensin II which has myriad effects on systemic cardiovascular function, inflammation, and cellular proliferation. Less well known is that macrophages and neutrophils make ACE in response to immune activation which has marked effects on myeloid cell function independent of angiotensin II. Here, we discuss both classical (angiotensin) and nonclassical functions of ACE and highlight mice called ACE 10/10 in which genetic manipulation increases ACE expression by macrophages and makes these mice much more resistant to models of tumors, infection, atherosclerosis, and Alzheimer's disease. In another model called NeuACE mice, neutrophils make increased ACE and these mice are much more resistant to infection. In contrast, ACE inhibitors reduce neutrophil killing of bacteria in mice and humans. Increased expression of ACE induces a marked increase in macrophage oxidative metabolism, particularly mitochondrial oxidation of lipids, secondary to increased peroxisome proliferator-activated receptor α expression, and results in increased myeloid cell ATP. ACE present in sperm has a similar metabolic effect, and the lack of ACE activity in these cells reduces both sperm motility and fertilization capacity. These nonclassical effects of ACE are not due to the actions of angiotensin II but to an unknown molecule, probably a peptide, that triggers a profound change in myeloid cell metabolism and function. Purifying and characterizing this peptide could offer a new treatment for several diseases and prove potentially lucrative.
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Affiliation(s)
- Kenneth E Bernstein
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
| | - DuoYao Cao
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Tomohiro Shibata
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Suguru Saito
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Ellen A Bernstein
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Erika Nishi
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Physiology, São Paulo School of Medicine, Universidade Federal de São Paulo, Sao Paulo, Brazil
| | - Michifumi Yamashita
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Warren G Tourtellotte
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Tuantuan V Zhao
- Research Oncology, Gilead Sciences, Foster City, California, USA
| | - Zakir Khan
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA; Institute for Myeloma & Bone Cancer Research, West Hollywood, California, USA
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de Melo IG, Tavares V, Pereira D, Medeiros R. Contribution of Endothelial Dysfunction to Cancer Susceptibility and Progression: A Comprehensive Narrative Review on the Genetic Risk Component. Curr Issues Mol Biol 2024; 46:4845-4873. [PMID: 38785560 PMCID: PMC11120512 DOI: 10.3390/cimb46050292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 05/09/2024] [Accepted: 05/13/2024] [Indexed: 05/25/2024] Open
Abstract
Venous thromboembolism (VTE) is a challenging clinical obstacle in oncological settings, marked by elevated incidence rates and resulting morbidity and mortality. In the context of cancer-associated thrombosis (CAT), endothelial dysfunction (ED) plays a crucial role in promoting a pro-thrombotic environment as endothelial cells lose their ability to regulate blood flow and coagulation. Moreover, emerging research suggests that this disorder may not only contribute to CAT but also impact tumorigenesis itself. Indeed, a dysfunctional endothelium may promote resistance to therapy and favour tumour progression and dissemination. While extensive research has elucidated the multifaceted mechanisms of ED pathogenesis, the genetic component remains a focal point of investigation. This comprehensive narrative review thus delves into the genetic landscape of ED and its potential ramifications on cancer progression. A thorough examination of genetic variants, specifically polymorphisms, within key genes involved in ED pathogenesis, namely eNOS, EDN1, ACE, AGT, F2, SELP, SELE, VWF, ICAM1, and VCAM1, was conducted. Overall, these polymorphisms seem to play a context-dependent role, exerting both oncogenic and tumour suppressor effects depending on the tumour and other environmental factors. In-depth studies are needed to uncover the mechanisms connecting these DNA variations to the pathogenesis of malignant diseases.
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Affiliation(s)
- Inês Guerra de Melo
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/Pathology and Laboratory Medicine Dep., Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto. CCC), 4200-072 Porto, Portugal; (I.G.d.M.); (V.T.)
- Faculty of Medicine of University of Porto (FMUP), 4200-072 Porto, Portugal
| | - Valéria Tavares
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/Pathology and Laboratory Medicine Dep., Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto. CCC), 4200-072 Porto, Portugal; (I.G.d.M.); (V.T.)
- Faculty of Medicine of University of Porto (FMUP), 4200-072 Porto, Portugal
- ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
| | - Deolinda Pereira
- Oncology Department, Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal;
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/Pathology and Laboratory Medicine Dep., Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto. CCC), 4200-072 Porto, Portugal; (I.G.d.M.); (V.T.)
- Faculty of Medicine of University of Porto (FMUP), 4200-072 Porto, Portugal
- ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
- Faculty of Health Sciences, Fernando Pessoa University, 4200-150 Porto, Portugal
- Research Department, Portuguese League Against Cancer (NRNorte), 4200-172 Porto, Portugal
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Wang Y, Jin B, Wu X, Xing J, Zhang B, Chen X, Liu X, Wan X, Du S. Exploration of prognostic and treatment markers in hepatocellular carcinoma via GPCR-related genes analysis. Heliyon 2024; 10:e29659. [PMID: 38694033 PMCID: PMC11058304 DOI: 10.1016/j.heliyon.2024.e29659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 05/03/2024] Open
Abstract
Background G protein-coupled receptors (GPCRs), the biggest family of signaling receptors, account for 34 % of all the drug targets approved by the Food and Drug Administration (FDA). It has been gradually recognized that GPCRs are of significance for tumorigenesis, but in-depth studies are still required to explore specific mechanisms. In this study, the role of GPCRs in hepatocellular carcinoma (HCC) was elucidated, and GPCR-related genes were employed for building a risk-score model for the prognosis and treatment efficacy prediction of HCC patients. Methods Patients' data on HCC were sourced from the Liver Hepatocellular Carcinoma-Japan (LIRI-JP) and The Cancer Genome Atlas (TCGA) databases, while GPCR-related genes were obtained from the Molecular Signatures Database (MSigDB). Univariant and multivariant Cox regression analyses, as well as least absolute shrinkage and selection operator (LASSO) were performed with the aim of identifying differentially expressed GPCR-related genes and grouping patients. Differential expression and functional enrichment analyses were performed; protein-protein interaction (PPI) mechanisms were explored; hub genes and micro ribonucleic acid (miRNA)-target gene regulatory networks were constructed. The tumor immune dysfunction and exclusion (TIDE) algorithm was utilized to evaluate immune infiltration levels and genetic variations. Sensitivity to immunotherapy and common antitumor drugs was predicted via the database Genomics of Drug Sensitivity in Cancer (GDSC). Results A GPCR-related risk score containing eight GPCR-related genes (atypical chemokine receptor 3 (ACKR3), C-C chemokine receptor type 3 (CCR3), CCR7, frizzled homolog 5 (FZD5), metabotropic glutamate receptor 8 (GRM8), hydroxycarboxylic acid receptor 1 (HCAR1), 5-hydroxytryptamine receptor 5A (HTR5A) and nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 6 (NLRP6)) was set up. In addition, patients were classified into groups with high and low risks. Patients in the high-risk group exhibited a worse prognosis but demonstrated a more favorable immunotherapy response rate compared with those in the low-risk group. Distinct sensitivity to chemotherapeutic drugs was observed. A clinical prediction model on the basis of GPCR-related risk scores was constructed. Areas under the curves (AUC) corresponding to one-, three- and five-year survival were 0.731, 0.765 and 0.731, respectively. Conclusions In this study, an efficient HCC prognostic prediction model was constructed by only GPCR-related genes, which are all potential targets for HCC treatment.
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Affiliation(s)
- Yuxin Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Bao Jin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Xiangan Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Jiali Xing
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Baoluhe Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Xiaokun Chen
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Xiao Liu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Xueshuai Wan
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
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Hedayati M, Garousi B, Rezaei Z, Nazerian Y, Yassaghi Y, Tavasol A, Zanjanbar DB, Sharifpour S, Golestani A, Bolideei M, Maleki F. Identifying SCC Lesions Capable of Spontaneous Regression by Using Immunohistochemistry: A Systematic Review and Meta-Analysis. Dermatol Pract Concept 2024; 14:dpc.1402a47. [PMID: 38810039 PMCID: PMC11135932 DOI: 10.5826/dpc.1402a47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/01/2023] [Indexed: 05/31/2024] Open
Abstract
INTRODUCTION Keratoacanthoma (KA) and squamous cell carcinoma (SCC) are two cutaneous conditions with morphological resemblance, which can complicate the diagnosis in some cases. Using immunohistochemistry staining of biomarkers could be beneficial in resolving this obstacle. OBJECTIVES We investigated a variety of biomarkers assessed in different studies in order to find the most important and helpful biomarkers for differentiation between SCC and lesions capable of spontaneous regression. METHODS MEDLINE via PubMed and Google Scholar database were used to identify relevant literature up to 15 June 2022. The aim of our analyses was to determine the capability of biomarkers to distinguish between SCC and lesions capable of spontaneous regression using calculated individual and pooled odds ratios (OR) and 95% confidence intervals (CI) and I2 tests. RESULTS Six potential biomarkers were CD10 with pooled OR= 0.006 (95% CI: 0.001-0.057) and I2=0%; COX-2 with pooled OR=0.089 (95% CI: 0.029-0.269) and I2=17.1%; elastic fibers with pooled OR= 6.69 (95% CI: 2.928-15.281) and I2=0%; IMP-3 with pooled OR=0.145 (95% CI: 0.021-1.001) and I2=44.5%; P53 with pooled OR=0.371 (95% CI: 0.188-0.733) and I2=55.9%; AT1R with OR=0.026 (95% CI: 0.006-0.107). CONCLUSIONS We suggest the utilization of the following IHC biomarkers for discrimination between lesions with spontaneous regression such as KA and SCC: CD10, COX-2, and elastic fibers.
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Affiliation(s)
| | - Behzad Garousi
- Department of Pathology, Karolinska Institute, Stockholm, Sweden
| | | | - Yasaman Nazerian
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Younes Yassaghi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arian Tavasol
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Dorsa Bahrami Zanjanbar
- Pharmaceutical Science Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Amir Golestani
- Students Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mansoor Bolideei
- The Center for Biomedical Research, Ministry of Education and Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Farajolah Maleki
- Non-Communicable Diseases Research Center, Ilam University of Medical Sciences, Ilam, Iran
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Yun Z, Shen Y, Yan X, Tian S, Wang J, Teo CS, Zhao H, Xue C, Dong Q, Hou L. Association between 19 medication use and risk of common cancers: A cross-sectional and Mendelian randomisation study. J Glob Health 2024; 14:04057. [PMID: 38487860 PMCID: PMC10940964 DOI: 10.7189/jogh.14.04057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2024] Open
Abstract
Background Previous studies have yielded inconsistent results concerning drug use and the risk of cancers. We conducted a large-scale cross-sectional study and a two-sample Mendelian randomisation (MR) study to reveal the causal effect between the use of 19 medications and the risk of four common cancers (breast, lung, colorectal, and prostate). Methods We obtained information on medication use and cancer diagnosis from National Health and Nutrition Examination Survey participants. After propensity score matching, we conducted survey-weighted multivariate logistic regression and restricted cubic spline analysis to assess the observed correlation between medication use and cancer while adjusting for multiple covariates. We also performed MR analysis to investigate causality based on summary data from genome-wide association studies on medication use and cancers. We performed sensitivity analyses, replication analysis, genetic correlation analysis, and reverse MR analysis to improve the reliability of MR findings. Results We found that the use of agents acting on the renin-angiotensin system was associated with reduced risk of prostate cancer (odds ratio (OR) = 0.42; 95% confidence interval (CI) = 0.27-0.63, P < 0.001), and there was a nonlinear association of 'decrease-to-increase-to-decrease' (P < 0.0001). The random-effects inverse variance weighted (IVW) model-based primary MR analysis (OR = 0.94, 95% CI = 0.91-0.97, P = 0.0007) and replication MR analysis (OR = 0.90, 95% CI = 0.85-0.96, P = 0.0006) both provided robust evidence of the causality of genetic liability for the use of agents acting on the renin-angiotensin system on a decreased risk of prostate cancer. Conclusions Our study provides robust evidence that the use of drugs acting on the renin-angiotensin system can reduce prostate cancer risk. Given the high prevalence of prostate cancer, these findings have important implications for drug selection and prostate cancer prevention in patients with cardiovascular disease.
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Affiliation(s)
- Zhangjun Yun
- Department of Oncology and Haematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- First School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yang Shen
- Department of Oncology and Haematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xiang Yan
- Department of Oncology and Haematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- First School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Shaodan Tian
- Department of Oncology and Haematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jing Wang
- Department of Oncology and Haematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Chiah Shean Teo
- School of Traditional and Complementary Medicine, Faculty of Medicine and Health Sciences, UCSI University, Kuala Lumpur, Malaysia
| | - Hongbin Zhao
- Department of Oncology and Haematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- First School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Chengyuan Xue
- Department of Oncology and Haematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- First School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Qing Dong
- Department of Oncology and Haematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Li Hou
- Department of Oncology and Haematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
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11
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Cui Y, Zhuang M, Huang Z, Guo Y, Chen F, Li Y, Long Y, Liu Y, Zeng G, Feng X, Chen X. An antihypertensive drug-AT1 inhibitor attenuated BRCA development promoted by chronic psychological stress via Ang II/PARP1/FN1 pathway. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167031. [PMID: 38253214 DOI: 10.1016/j.bbadis.2024.167031] [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: 09/14/2023] [Revised: 01/04/2024] [Accepted: 01/15/2024] [Indexed: 01/24/2024]
Abstract
Chronic psychological stress contributes to the occurrence of cancer and activates the renin-angiotensin system (RAS). However, the mechanisms by which RAS promotes the progression of breast cancer (BRCA) under chronic psychological stress are remain unknown. In this study, we observed elevated levels of Angiotensin II (Ang II) in both serum and BRCA tissue under chronic stress, leading to accelerated BRCA growth in a mouse model. An antihypertensive drug, candesartan (an AT1 inhibitor), effectively attenuated Ang II-induced cell proliferation and metastasis. Utilizing mass spectrometry and weighted gene co-expression network analysis (WGCNA), we identified fibronectin 1 (FN1) as the hub protein involved in chronic stress-Ang II/AT1 axis. Focal adhesion pathway was identified as a downstream signaling pathway activated during the progression of chronic stress. Depletion of FN1 significantly attenuated Ang II-induced proliferation and metastasis of BRCA cells. Poly (ADP-ribose) polymerase 1 (PARP1) was found to bind to the DNA promoter of FN1, leading to the transcription of FN1. Ang II upregulated PARP1 expression, resulting in increased FN1 levels. Recombinant FN1 partially restored the progress of BRCA malignancy induced by the Ang II/PARP1 pathway. In vivo, candesartan reversed the progressive effect of chronic psychological stress on BRCA. In clinical samples, Ang II levels in both serum and tumor tissues are higher in stressed patients compared to control patients. Serum Ang II levels were positively correlated with chronic stress indicators. In conclusion, our study demonstrated that chronic psychological stress accelerates the malignancy of BRCA, and the AT1 inhibitor candesartan counteracts these effects by suppressing the Ang II-AT1 axis and the downstream PARP1/FN1/focal adhesion pathway.
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Affiliation(s)
- Yuqing Cui
- The Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China; The Department of Oncology, The First Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Ming Zhuang
- The Department Radiotherapy Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Zheping Huang
- Women & Infants Hospital of Rhode Island & Warren Alpert Medical School of Brown University, Providence, RI 02905, USA
| | - Yan Guo
- The Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China; The Department of Oncology, The First Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Fengzhi Chen
- The Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Yangyang Li
- The Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Yuanhui Long
- The Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Ying Liu
- The Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Guangchun Zeng
- The Department of Pathology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Xujing Feng
- The Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Xuesong Chen
- The Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China; The Department of Oncology, The First Affiliated Hospital of Harbin Medical University, Harbin 150081, China.
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12
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Omidkhah N, Hadizadeh F, Ghodsi R, Kesharwani P, Sahebkar A. In silico Evaluation of NO-Sartans against SARS-CoV-2. Curr Drug Discov Technol 2024; 21:e050324227669. [PMID: 38445698 DOI: 10.2174/0115701638279362240223070810] [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: 10/20/2023] [Revised: 01/16/2024] [Accepted: 01/29/2024] [Indexed: 03/07/2024]
Abstract
INTRODUCTION Numerous clinical trials are currently investigating the potential of nitric oxide (NO) as an antiviral agent against coronaviruses, including SARS-CoV-2. Additionally, some researchers have reported positive effects of certain Sartans against SARS-CoV-2. METHOD Considering the impact of NO-Sartans on the cardiovascular system, we have compiled information on the general structure, synthesis methods, and biological studies of synthesized NOSartans. In silico evaluation of all NO-Sartans and approved sartans against three key SARS-CoV- -2 targets, namely Mpro (PDB ID: 6LU7), NSP16 (PDB ID: 6WKQ), and ACE-2 (PDB ID: 1R4L), was performed using MOE. RESULTS Almost all NO-Sartans and approved sartans demonstrated promising results in inhibiting these SARS-CoV-2 targets. Compound 36 (CLC-1280) showed the best docking scores against the three evaluated targets and was further evaluated using molecular dynamics (MD) simulations. CONCLUSION Based on our in silico studies, CLC-1280 (a Valsartan dinitrate) has the potential to be considered as an inhibitor of the SARS-CoV-2 virus. However, further in vitro and in vivo evaluations are necessary for the drug development process.
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Affiliation(s)
- Negar Omidkhah
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzin Hadizadeh
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Razieh Ghodsi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard University, New Delhi, 110062, India
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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13
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Pandey S, Kalaria A, Jhaveri KD, Herrmann SM, Kim AS. Management of hypertension in patients with cancer: challenges and considerations. Clin Kidney J 2023; 16:2336-2348. [PMID: 38046043 PMCID: PMC10689173 DOI: 10.1093/ckj/sfad195] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Indexed: 12/05/2023] Open
Abstract
The survival rates of many cancers have significantly improved due to recent advancements in cancer screening and therapeutics. Although better cancer outcomes are encouraging, additional health challenges have surfaced, the utmost of which is the burden imposed by various cardiovascular and renal toxicities of anticancer therapies. To improve the overall outcome of patients with cancer, it is essential to understand and manage these treatment-related adverse effects. The cardiovascular side effects of antineoplastic therapies are well-known and include left ventricular dysfunction, heart failure, myocardial ischaemia, QT prolongation, arrhythmia and hypertension. Among these, hypertension is the most common complication, prevalent in about 40% of all cancer patients, yet frequently overlooked and undertreated. This review explores the intricate connection between cancer and hypertension and provides distinct approaches to diagnosing, monitoring and managing hypertension in patients with cancer. We also outline the challenges and considerations that are relevant to the care of patients receiving anticancer drugs with prohypertensive potential.
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Affiliation(s)
- Shubhi Pandey
- Department of Internal Medicine, Calhoun Cardiology Center, University of Connecticut Health, Farmington, CT, USA
- University of Connecticut School of Medicine, Farmington, CT, USA
| | - Amar Kalaria
- University of Connecticut School of Medicine, Farmington, CT, USA
| | - Kenar D Jhaveri
- Division of Kidney Diseases and Hypertension, Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA
| | - Sandra M Herrmann
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Agnes S Kim
- Department of Internal Medicine, Calhoun Cardiology Center, University of Connecticut Health, Farmington, CT, USA
- University of Connecticut School of Medicine, Farmington, CT, USA
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14
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Hassani B, Attar Z, Firouzabadi N. The renin-angiotensin-aldosterone system (RAAS) signaling pathways and cancer: foes versus allies. Cancer Cell Int 2023; 23:254. [PMID: 37891636 PMCID: PMC10604988 DOI: 10.1186/s12935-023-03080-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 09/20/2023] [Indexed: 10/29/2023] Open
Abstract
The renin-angiotensin-aldosterone system (RAAS), is an old system with new fundamental roles in cancer biology which influences cell growth, migration, death, and metastasis. RAAS signaling enhances cell proliferation in malignancy directly and indirectly by affecting tumor cells and modulating angiogenesis. Cancer development may be influenced by the balance between the ACE/Ang II/AT1R and the ACE2/Ang 1-7/Mas receptor pathways. The interactions between Ang II/AT1R and Ang I/AT2R as well as Ang1-7/Mas and alamandine/MrgD receptors in the RAAS pathway can significantly impact the development of cancer. Ang I/AT2R, Ang1-7/Mas, and alamandine/MrgD interactions can have anticancer effects while Ang II/AT1R interactions can be involved in the development of cancer. Evidence suggests that inhibitors of the RAAS, which are conventionally used to treat cardiovascular diseases, may be beneficial in cancer therapies.Herein, we aim to provide a thorough description of the elements of RAAS and their molecular play in cancer. Alongside this, the role of RAAS components in sex-dependent cancers as well as GI cancers will be discussed with the hope of enlightening new venues for adjuvant cancer treatment.
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Affiliation(s)
- Bahareh Hassani
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zeinab Attar
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Negar Firouzabadi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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15
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Jahankhani K, Ahangari F, Adcock IM, Mortaz E. Possible cancer-causing capacity of COVID-19: Is SARS-CoV-2 an oncogenic agent? Biochimie 2023; 213:130-138. [PMID: 37230238 PMCID: PMC10202899 DOI: 10.1016/j.biochi.2023.05.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 04/24/2023] [Accepted: 05/22/2023] [Indexed: 05/27/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown diverse life-threatening effects, most of which are considered short-term. In addition to its short-term effects, which has claimed many millions of lives since 2019, the long-term complications of this virus are still under investigation. Similar to many oncogenic viruses, it has been hypothesized that SARS-CoV-2 employs various strategies to cause cancer in different organs. These include leveraging the renin angiotensin system, altering tumor suppressing pathways by means of its nonstructural proteins, and triggering inflammatory cascades by enhancing cytokine production in the form of a "cytokine storm" paving the way for the emergence of cancer stem cells in target organs. Since infection with SARS-CoV-2 occurs in several organs either directly or indirectly, it is expected that cancer stem cells may develop in multiple organs. Thus, we have reviewed the impact of coronavirus disease 2019 (COVID-19) on the vulnerability and susceptibility of specific organs to cancer development. It is important to note that the cancer-related effects of SARS-CoV-2 proposed in this article are based on the ability of the virus and its proteins to cause cancer but that the long-term consequences of this infection will only be illustrated in the long run.
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Affiliation(s)
- Kasra Jahankhani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ahangari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ian M Adcock
- Airways Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom; Immune Health Program at Hunter Medical Research Institute and the College of Health and Medicine at the University of Newcastle, Australia
| | - Esmaeil Mortaz
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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16
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Chiu TJ, Chen CH, Chen YJ, Wee Y, Wang CS, Luo SD. Prognosis of Midkine and AT1R expression in resectable head and neck squamous cell carcinoma. Cancer Cell Int 2023; 23:212. [PMID: 37743493 PMCID: PMC10518915 DOI: 10.1186/s12935-023-03060-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 09/08/2023] [Indexed: 09/26/2023] Open
Abstract
BACKGROUND Research studies have demonstrated that Midkine (MDK) can influence the expression and activity of Renin-angiotensin system (RAS) components. Angiotensin II is involved in tumor growth and angiogenesis in different cancers. We previously observed Angiotensin II receptor blockers (ARBs) improve the survival rates of patients with oral cancers. These findings have prompted us to investigate whether MDK can influence the RAS pathway, mainly through its association with angiotensin II type 1 receptor (AT1R), which contributes to the observed poor prognosis in head and neck squamous cell carcinoma (HNSCC) patients. METHODS MDK and AT1R expressions were examined in 150 HNSCC patients post-operation by immunohistochemical staining between 1 January 2010 and 31 December 2016. We tested the over-expression and silencing of MDK to evaluate the AT1R expression and functional biological assays in HNSCC cell lines HSC-3 and SAS. RESULTS Positive expression of MDK is correlated with positive AT1R expression. MDK predicted poor NSCC patients' survival. Silencing MDK could suppress AT1R and pAKT expression and reduce the growth, migration, and invasion of HNSCC cells. ARB also inhibits MDK stimulating HNSCC cell proliferation. Overexpression of MDK could upregulate AT1R and pAKT. CONCLUSIONS MDK is an independent prognostic factor of HNSCC post-operation, and AT1R regulates HNSCC cell growth, invasion, and migration. Positive MDK and AT1R expressions are highly correlated. Mechanistically, the interaction between MDK and AT1R is crucial for MDK-mediated cell viability, and inhibiting AT1R can effectively counteract or abolish these effects. Furthermore, MDK exerts a regulatory role in the expression of AT1R, as well as in the growth and motility of HNSCC cells. These findings highlight the involvement of the interaction between MDK, AT1R, and the pAkt signaling pathways in HNSCC cell viability growth.
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Affiliation(s)
- Tai-Jan Chiu
- Department of Hematology‑Oncology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan
| | - Chang-Han Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yi-Ju Chen
- Kaohsiung Cancer Prevention and Screening Center, Kaohsiung, 833, Taiwan
| | - Yinshen Wee
- Department of Pathology, University of Utah, Salt Lake City, UT, 84112, USA
| | - Ching-Shuen Wang
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Sheng-Dean Luo
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan.
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, 33302, Taiwan.
- School of Traditional Chinese Medicine, Chang Gung University College of Medicine, Taoyuan, 33302, Taiwan.
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17
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Masoudkabir F, Mohammadifard N, Mani A, Ignaszewski A, Davis MK, Vaseghi G, Mansourian M, Franco C, Gotay C, Sarrafzadegan N. Shared Lifestyle-Related Risk Factors of Cardiovascular Disease and Cancer: Evidence for Joint Prevention. ScientificWorldJournal 2023; 2023:2404806. [PMID: 37520844 PMCID: PMC10386903 DOI: 10.1155/2023/2404806] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 02/25/2023] [Accepted: 06/09/2023] [Indexed: 08/01/2023] Open
Abstract
Cardiovascular disease (CVD) and cancer are leading causes of mortality and morbidity worldwide and are the major focus of the World Health Organization's joint prevention programs. While, diverse diseases, CVD and cancer, have many similarities. These include common lifestyle-related risk factors and shared environmental, metabolic, cellular, inflammatory, and genetic pathways. In this review, we will discuss the shared lifestyle-related and environmental risk factors central to both diseases and how the strategies commonly used to prevent atherosclerotic vascular disease can be applied to cancer prevention.
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Affiliation(s)
- Farzad Masoudkabir
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Noushin Mohammadifard
- Hypertension Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Arya Mani
- Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Andrew Ignaszewski
- Division of Cardiology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Margot K. Davis
- Division of Cardiology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Golnaz Vaseghi
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marjan Mansourian
- Epidemiology and Biostatistics Department, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Christopher Franco
- Division of Cardiology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Carolyn Gotay
- School of Population & Public Health, The University of British Columbia, Vancouver, BC, Canada
| | - Nizal Sarrafzadegan
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
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Uruski P, Matuszewska J, Leśniewska A, Rychlewski D, Niklas A, Mikuła-Pietrasik J, Tykarski A, Książek K. An integrative review of nonobvious puzzles of cellular and molecular cardiooncology. Cell Mol Biol Lett 2023; 28:44. [PMID: 37221467 DOI: 10.1186/s11658-023-00451-y] [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: 02/22/2023] [Accepted: 04/17/2023] [Indexed: 05/25/2023] Open
Abstract
Oncologic patients are subjected to four major treatment types: surgery, radiotherapy, chemotherapy, and immunotherapy. All nonsurgical forms of cancer management are known to potentially violate the structural and functional integrity of the cardiovascular system. The prevalence and severity of cardiotoxicity and vascular abnormalities led to the emergence of a clinical subdiscipline, called cardiooncology. This relatively new, but rapidly expanding area of knowledge, primarily focuses on clinical observations linking the adverse effects of cancer therapy with deteriorated quality of life of cancer survivors and their increased morbidity and mortality. Cellular and molecular determinants of these relations are far less understood, mainly because of several unsolved paths and contradicting findings in the literature. In this article, we provide a comprehensive view of the cellular and molecular etiology of cardiooncology. We pay particular attention to various intracellular processes that arise in cardiomyocytes, vascular endothelial cells, and smooth muscle cells treated in experimentally-controlled conditions in vitro and in vivo with ionizing radiation and drugs representing diverse modes of anti-cancer activity.
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Affiliation(s)
- Paweł Uruski
- Department of Hypertensiology, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland
| | - Julia Matuszewska
- Department of Pathophysiology of Ageing and Civilization Diseases, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland
| | - Aleksandra Leśniewska
- Department of Pathophysiology of Ageing and Civilization Diseases, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland
| | - Daniel Rychlewski
- Department of Pathophysiology of Ageing and Civilization Diseases, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland
| | - Arkadiusz Niklas
- Department of Hypertensiology, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland
| | - Justyna Mikuła-Pietrasik
- Department of Pathophysiology of Ageing and Civilization Diseases, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland
| | - Andrzej Tykarski
- Department of Hypertensiology, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland
| | - Krzysztof Książek
- Department of Pathophysiology of Ageing and Civilization Diseases, Poznań University of Medical Sciences, Długa ½ Str., 61-848, Poznan, Poland.
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19
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Nguyen NTH, Nguyen PA, Huang CW, Wang CH, Lin MC, Hsu MH, Bao HB, Chien SC, Yang HC. Renin-Angiotensin-Aldosterone System Inhibitors and Development of Gynecologic Cancers: A 23 Million Individual Population-Based Study. Int J Mol Sci 2023; 24:ijms24043814. [PMID: 36835224 PMCID: PMC9968233 DOI: 10.3390/ijms24043814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 02/17/2023] Open
Abstract
The chronic receipt of renin-angiotensin-aldosterone system (RAAS) inhibitors including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been assumed to be associated with a significant decrease in overall gynecologic cancer risks. This study aimed to investigate the associations of long-term RAAS inhibitors use with gynecologic cancer risks. A large population-based case-control study was conducted from claim databases of Taiwan's Health and Welfare Data Science Center (2000-2016) and linked with Taiwan Cancer Registry (1979-2016). Each eligible case was matched with four controls using propensity matching score method for age, sex, month, and year of diagnosis. We applied conditional logistic regression with 95% confidence intervals to identify the associations of RAAS inhibitors use with gynecologic cancer risks. The statistical significance threshold was p < 0.05. A total of 97,736 gynecologic cancer cases were identified and matched with 390,944 controls. The adjusted odds ratio for RAAS inhibitors use and overall gynecologic cancer was 0.87 (95% CI: 0.85-0.89). Cervical cancer risk was found to be significantly decreased in the groups aged 20-39 years (aOR: 0.70, 95% CI: 0.58-0.85), 40-64 years (aOR: 0.77, 95% CI: 0.74-0.81), ≥65 years (aOR: 0.87, 95% CI: 0.83-0.91), and overall (aOR: 0.81, 95% CI: 0.79-0.84). Ovarian cancer risk was significantly lower in the groups aged 40-64 years (aOR: 0.76, 95% CI: 0.69-0.82), ≥65 years (aOR: 0.83, 95% CI: 0.75-092), and overall (aOR: 0.79, 95% CI: 0.74-0.84). However, a significantly increased endometrial cancer risk was observed in users aged 20-39 years (aOR: 2.54, 95% CI: 1.79-3.61), 40-64 years (aOR: 1.08, 95% CI: 1.02-1.14), and overall (aOR: 1.06, 95% CI: 1.01-1.11). There were significantly reduced risks of gynecologic cancers with ACEIs users in the groups aged 40-64 years (aOR: 0.88, 95% CI: 0.84-0.91), ≥65 years (aOR: 0.87, 95% CI: 0.83-0.90), and overall (aOR: 0.88, 95% CI: 0.85-0.80), and ARBs users aged 40-64 years (aOR: 0.91, 95% CI: 0.86-0.95). Our case-control study demonstrated that RAAS inhibitors use was associated with a significant decrease in overall gynecologic cancer risks. RAAS inhibitors exposure had lower associations with cervical and ovarian cancer risks, and increased endometrial cancer risk. ACEIs/ARBs use was found to have a preventive effect against gynecologic cancers. Future clinical research is needed to establish causality.
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Affiliation(s)
- Nhi Thi Hong Nguyen
- School of Health Care Administration, College of Management, Taipei Medical University, Taipei 11031, Taiwan
- Health Personnel Training Institute, University of Medicine and Pharmacy, Hue University, Hue 491-20, Vietnam
| | - Phung-Anh Nguyen
- Clinical Data Center, Office of Data Science, Taipei Medical University, Taipei 106339, Taiwan
- Clinical Big Data Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Chih-Wei Huang
- International Center for Health Information Technology (ICHIT), College of Medical Science and Technology, Taipei Medical University, Taipei 106339, Taiwan
| | - Ching-Huan Wang
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 106339, Taiwan
- Biomedical Informatics & Data Science (BIDS) Section, School of Medicine, Johns Hopkins University, 2024 E Monument St, Suite 1-200, Baltimore, MD 21205, USA
| | - Ming-Chin Lin
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 106339, Taiwan
- Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235041, Taiwan
- Taipei Neuroscience Institute, Taipei Medical University, Taipei 11031, Taiwan
| | - Min-Huei Hsu
- Clinical Data Center, Office of Data Science, Taipei Medical University, Taipei 106339, Taiwan
- Graduate Institute of Data Science, College of Management, Taipei Medical University, Taipei 11031, Taiwan
| | - Hoang Bui Bao
- Health Personnel Training Institute, University of Medicine and Pharmacy, Hue University, Hue 491-20, Vietnam
- Internal Medicine Department, University of Medicine and Pharmacy, Hue University, Hue 491-20, Vietnam
| | - Shuo-Chen Chien
- International Center for Health Information Technology (ICHIT), College of Medical Science and Technology, Taipei Medical University, Taipei 106339, Taiwan
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 106339, Taiwan
| | - Hsuan-Chia Yang
- Clinical Big Data Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- International Center for Health Information Technology (ICHIT), College of Medical Science and Technology, Taipei Medical University, Taipei 106339, Taiwan
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 106339, Taiwan
- Research Center of Big Data and Meta-Analysis, Wan Fang Hospital, Taipei Medical University, Taipei 116079, Taiwan
- Correspondence:
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Tuli HS, Vashishth K, Sak K, Mohapatra RK, Dhama K, Kumar M, Abbas Z, Lata K, Yerer MB, Garg VK, Sharma AK, Kaur G. Anticancer Role of Natural Phenolic Acids by Targeting Angiotensin-Converting Enzyme (ACE). ADVANCES IN BIOCHEMISTRY IN HEALTH AND DISEASE 2023:465-481. [DOI: 10.1007/978-3-031-23621-1_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/26/2024]
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21
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Alaaeldin R, Ali FEM, Bekhit AA, Zhao QL, Fathy M. Inhibition of NF-kB/IL-6/JAK2/STAT3 Pathway and Epithelial-Mesenchymal Transition in Breast Cancer Cells by Azilsartan. Molecules 2022; 27:7825. [PMID: 36431925 PMCID: PMC9693603 DOI: 10.3390/molecules27227825] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/09/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
Metastatic breast cancer is an incurable form of breast cancer that exhibits high levels of epithelial-mesenchymal transition (EMT) markers. Angiotensin II has been linked to various signaling pathways involved in tumor cell growth and metastasis. The aim of this study is to investigate, for the first time, the anti-proliferative activity of azilsartan, an angiotensin II receptor blocker, against breast cancer cell lines MCF-7 and MDA-MB-231 at the molecular level. Cell viability, cell cycle, apoptosis, colony formation, and cell migration assays were performed. RT-PCR and western blotting analysis were used to explain the molecular mechanism. Azilsartan significantly decreased the cancer cells survival, induced apoptosis and cell cycle arrest, and inhibited colony formation and cell migration abilities. Furthermore, azilsartan reduced the mRNA levels of NF-kB, TWIST, SNAIL, SLUG and bcl2, and increased the mRNA level of bax. Additionally, azilsartan inhibited the expression of IL-6, JAK2, STAT3, MMP9 and bcl2 proteins, and increased the expression of bax, c-PARP and cleaved caspase 3 protein. Interestingly, it reduced the in vivo metastatic capacity of MDA-MBA-231 breast cancer cells. In conclusion, the present study revealed, for the first time, the anti-proliferative, apoptotic, anti-migration and EMT inhibition activities of azilsartan against breast cancer cells through modulating NF-kB/IL-6/JAK2/STAT3/MMP9, TWIST/SNAIL/SLUG and apoptosis signaling pathways.
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Affiliation(s)
- Rania Alaaeldin
- Department of Biochemistry, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt
| | - Fares E. M. Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | | | - Qing-Li Zhao
- Department of Radiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
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22
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Jeon HL, Lee SH, Nam JH, Shin JY. Cancer risk associated with the use of valsartan in Korea: A nationwide cohort study. Cancer Epidemiol 2022; 80:102245. [PMID: 36087359 DOI: 10.1016/j.canep.2022.102245] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 08/20/2022] [Accepted: 08/26/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Despite valsartan's widespread use, few studies have explored its potential carcinogenicity. We evaluated the association between valsartan and cancer. METHODS We conducted a retrospective cohort study using data from 2002 to 2015 gathered from the National Health Insurance database. Patients with hypertension aged ≥ 30 who used valsartan or other angiotensin II receptor blockers (ARBs) were included. Eligible patients were those with no prior history of the use of any ARBs, diagnosis of cancer, or organ transplantation in the 4 years predating their first use of the drugs of interest. The primary and secondary outcomes included the occurrence of all cancers and site-specific solid cancers, respectively. After applying propensity score (PS) matching, Cox regression was used to calculate the hazard ratios (HRs) and 95 % confidence intervals (CIs). RESULTS A total of 1,550,734 individuals were identified as new users of valsartan or other ARBs. Of the 153,047 valsartan users, 16,047 were diagnosed with cancer. No increased risk of overall cancer was observed in valsartan users as compared to other ARB users (aHR = 1.00; 95 % CI, 0.98-1.02). Valsartan was, however, associated with a slightly elevated risk of liver (aHR = 1.09; 95 % CI, 1.01-1.16) and kidney cancer (aHR = 1.11; 95 % CI, 1.02-1.22). CONCLUSION Compared with other ARBs, valsartan did not increase the risk of overall cancer. A slightly increased risk for some solid cancers was associated with valsartan use, though the absolute rate difference was small.
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Affiliation(s)
- Ha-Lim Jeon
- School of Pharmacy and Institute of New Drug Development, Jeonbuk National University, Jeonju, Republic of Korea
| | - Seon Hee Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - Jin Hyun Nam
- Division of Big Data Science, Korea University Sejong Campus, Sejong, Republic of Korea
| | - Ju-Young Shin
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea; Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, Republic of Korea; Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, Republic of Korea.
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23
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da Silva FA, Rodrigues-Ribeiro L, Melo-Braga MN, Passos-Silva DG, Sampaio WO, Gorshkov V, Kjeldsen F, Verano-Braga T, Santos RAS. Phosphoproteomic studies of alamandine signaling in CHO-MrgD and human pancreatic carcinoma cells: An antiproliferative effect is unveiled. Proteomics 2022; 22:e2100255. [PMID: 35652611 DOI: 10.1002/pmic.202100255] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 04/16/2022] [Accepted: 05/30/2022] [Indexed: 11/06/2022]
Abstract
Alamandine is a heptapeptide from the renin-angiotensin system (RAS) with similar structure/function to angiotensin-(1-7) [ang-(1-7)], but they act via different receptors. It remains elusive whether alamandine is an antiproliferative agent like ang-(1-7). The goal of this study was to evaluate the potential antiproliferative activity of alamandine and the underlying cellular signaling. We evaluated alamandine effect in the tumoral cell lines Mia PaCa-2 and A549, and in the nontumoral cell lines HaCaT, CHO and CHO transfected with the alamandine receptor MrgD (CHO-MrgD). Alamandine was able to reduce the proliferation of the tumoral cell lines in a MrgD-dependent fashion. We did not observe any effect in the nontumoral cell lines tested. We also performed proteomics and phosphoproteomics to study the alamandine signaling in Mia PaCa-2 and CHO-MrgD. Data suggest that alamandine induces a shift from anaerobic to aerobic metabolism in the tumoral cells, induces a negative regulation of PI3K/AKT/mTOR pathway and activates the transcriptional factor FoxO1; events that could explain, at least partially, the observed antiproliferative effect of alamandine. This study provides for the first time a comprehensive investigation of the alamandine signaling in tumoral (Mia PaCa-2) and nontumoral (CHO-MrgD) cells, highlighting the antiproliferative activity of alamandine/MrgD and its possible antitumoral effect.
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Affiliation(s)
- Filipe Alex da Silva
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- National Institute of Science and Technology in Nanobiopharmaceutics, Belo Horizonte, Minas Gerais, Brazil
| | - Lucas Rodrigues-Ribeiro
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- National Institute of Science and Technology in Nanobiopharmaceutics, Belo Horizonte, Minas Gerais, Brazil
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Marcella Nunes Melo-Braga
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- National Institute of Science and Technology in Nanobiopharmaceutics, Belo Horizonte, Minas Gerais, Brazil
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Danielle Gomes Passos-Silva
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- National Institute of Science and Technology in Nanobiopharmaceutics, Belo Horizonte, Minas Gerais, Brazil
| | - Walkyria Oliveira Sampaio
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- National Institute of Science and Technology in Nanobiopharmaceutics, Belo Horizonte, Minas Gerais, Brazil
| | - Vladimir Gorshkov
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Syddanmark, Denmark
| | - Frank Kjeldsen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Syddanmark, Denmark
| | - Thiago Verano-Braga
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- National Institute of Science and Technology in Nanobiopharmaceutics, Belo Horizonte, Minas Gerais, Brazil
| | - Robson Augusto Souza Santos
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- National Institute of Science and Technology in Nanobiopharmaceutics, Belo Horizonte, Minas Gerais, Brazil
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24
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Berger S, Bjark TH, Midtvedt K, Andersen R. Regression of a venous malformation during ACE-inhibitor treatment for hypertension. J Vasc Surg Cases Innov Tech 2022; 8:657-659. [PMID: 36262918 PMCID: PMC9574577 DOI: 10.1016/j.jvscit.2022.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/09/2022] [Accepted: 09/02/2022] [Indexed: 10/26/2022] Open
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25
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Munday JS, Odom T, Dittmer KE, Wetzel S, Hillmer K, Tan ST. Multimodal Blockade of the Renin-Angiotensin System Is Safe and Is a Potential Cancer Treatment for Cats. Vet Sci 2022; 9:vetsci9080411. [PMID: 36006326 PMCID: PMC9413835 DOI: 10.3390/vetsci9080411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/21/2022] [Accepted: 08/04/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary As activation of the renin-angiotensin system (RAS) promotes cancer cell growth, medications that inhibit RAS activation could reduce cancer progression. However, studies in people in which RAS has been inhibited by a single treatment have not been consistently beneficial, possibly as RAS can be activated by many different cellular pathways. Multiple treatments have been used to more consistently block RAS in people, but such multimodal treatments have never previously been evaluated in veterinary species. In the present study, the safety of multimodal RAS inhibition using a combination of five treatments was assessed in six cats with cancer. Cats were treated for 8 weeks and none of the cats developed low blood pressure, evidence of kidney or liver disease, or significant adverse effects. Of the six cats enrolled in the study, one cat was withdrawn from the study due to difficulties administering the medications and another cat died of an unrelated cause. Two cats were euthanatized due to cancer progression during the study period while two cats completed the 8-week treatment period. The study showed that a multimodal blockade of RAS has the potential to be a safe and cost-effective treatment for cancer in cats. Abstract The role of the renin-angiotensin system (RAS) in cancer growth and progression is well recognized in humans. However, studies on RAS inhibition with a single agent have not shown consistent anticancer effects, potentially due to the neoplastic cells utilizing alternative pathways for RAS activation. To achieve more complete RAS inhibition, multimodal therapy with several medications that simultaneously block multiple steps in the RAS has been developed for use in humans. In the present study, the safety of multimodal RAS inhibition using atenolol, benazepril, metformin, curcumin, and meloxicam was assessed in six cats with squamous cell carcinomas. Cats were treated for 8 weeks, with blood pressure measured and blood sampled five times during the treatment period. None of the cats developed hypotension, azotemia, or increased serum liver enzyme concentrations. The packed cell volume of one cat decreased to just below the reference range during treatment. One cat was reported to have increased vomiting, although this occurred infrequently. One cat was withdrawn from the study due to difficulties administering the medications, and another cat died of an unrelated cause. Two cats were euthanatized during the study period due to cancer progression. Two cats completed the 8-week study period. One was subsequently euthanized due to cancer progression while the other cat is still alive 32 weeks after entering the study and is still receiving the multimodal blockade of the RAS. This is the first evaluation of multimodal blockade of the RAS in veterinary species. The study showed that the treatment is safe, with only mild adverse effects observed in two treated cats. Due to the small number of cats, the efficacy of treatment could not be evaluated. However, evidence from human studies suggests that a multimodal blockade of RAS could be a safe and cost-effective treatment option for cancer in cats.
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Affiliation(s)
- John S. Munday
- School of Veterinary Science, Massey University, Palmerston North 4410, New Zealand
- Correspondence:
| | - Thomas Odom
- School of Veterinary Science, Massey University, Palmerston North 4410, New Zealand
| | - Keren E. Dittmer
- School of Veterinary Science, Massey University, Palmerston North 4410, New Zealand
| | - Sarah Wetzel
- School of Veterinary Science, Massey University, Palmerston North 4410, New Zealand
| | | | - Swee T. Tan
- Gillies McIndoe Research Institute, Wellington 7184, New Zealand
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26
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Sapena V, Iavarone M, Boix L, Facchetti F, Guarino M, Sanduzzi Zamparelli M, Granito A, Samper E, Scartozzi M, Corominas J, Marisi G, Díaz A, Casadei-Gardini A, Gramantieri L, Lampertico P, Morisco F, Torres F, Bruix J, Reig M. Polymorphism AGT2 (rs4762) is involved in the development of dermatologic events: Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib. World J Hepatol 2022; 14:1438-1458. [PMID: 36158918 PMCID: PMC9376774 DOI: 10.4254/wjh.v14.i7.1438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/24/2022] [Accepted: 07/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Dermatologic adverse events (DAEs) are associated with a better outcome in patients with hepatocellular carcinoma (HCC) irrespective of the therapeutic agent received. The exact mechanisms associated with the development of DAEs are unknown although several studies point to direct toxicity of tyrosine kinase inhibitors (TKIs) to the skin or an immune-mediated reaction triggered by the oncologic treatment. As is the case in other conditions, individual genetic variants may partially explain a higher risk of DAEs. AIM To evaluate the contribution of several gene variants to the risk of developing DAEs in HCC patients treated with TKIs. METHODS We first analyzed 27 single-nucleotide polymorphisms (SNPs) from 12 genes selected as potential predictors of adverse event (AE) development in HCC patients treated with sorafenib [Barcelona Clinic Liver Cancer 1 (BCLC1) cohort]. Three additional cohorts were analyzed for AGT1 (rs699) and AGT2 (rs4762) polymorphisms-initially identified as predictors of DAEs: BCLC2 (n = 79), Northern Italy (n = 221) and Naples (n = 69) cohorts, respectively. The relation between SNPs and DAEs and death were assessed by univariate and multivariate Cox regression models, and presented with hazard ratios and their 95% confidence intervals (95%CI). RESULTS The BCLC1 cohort showed that patients with arterial hypertension (AHT) (HR = 1.61; P value = 0.007) and/or AGT SNPs had an increased risk of DAEs. Thereafter, AGT2 (rs4762) AA genotype was found to be linked to a statistically significant increased probability of DAEs (HR = 5.97; P value = 0.0201, AA vs GG) in the Northern Italy cohort by multivariate analysis adjusted for BCLC stage, ECOG-PS, diabetes and AHT. The value of this genetic marker was externally validated in the cohort combining the BCLC1, BCLC2 and Naples cohorts [HR = 3.12 (95%CI: 1.2-8.14), P value = 0.0199, AGT2 (rs4762) AA vs AG genotype and HR = 2.73 (95%CI: 1.18-6.32) P value = 0.0188, AGT2 (rs4762) AA vs GG genotype]. None of the other gene variants tested were found to be associated with the risk of DAE development. CONCLUSION DAE development in HCC patients receiving TKIs could be explained by the AGT2 (rs4762) gene variant. If validated in other anti-oncogenic treatments, it might be considered a good prognosis marker.
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Affiliation(s)
- Víctor Sapena
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
| | - Massimo Iavarone
- Division of Gastroenterology and Hepatology, Foundation Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy
| | - Loreto Boix
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
| | - Floriana Facchetti
- Gastroenterology and Hepatology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan 20100, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples "Federico II", Napoli 80100, Italy
| | - Marco Sanduzzi Zamparelli
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
- Department of Clinical Medicine and Surgery, Gastroenterology and Hepatology, Federico II University of Naples, Naples 80131, Italy
| | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Azienda Ospedaliero-Universitaria di Bologna, Bologna 40139, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40139, Italy
| | - Esther Samper
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
| | - Mario Scartozzi
- Department of Medical Oncology, University of Cagliari, Cagliari 45698, Italy
| | - Josep Corominas
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
| | - Giorgia Marisi
- Biosciences Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica, Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori", Meldola 47014, Italy
| | - Alba Díaz
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
- Department of Pathology, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona 08036, Spain
| | - Andrea Casadei-Gardini
- School of Medicine, Vita-Salute San Raffaele University, Milan 20132, Italy
- Unit of Oncology, Università Vita-Salute, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica-San Raffaele Scientific Institute, Milan 20132, Italy
| | - Laura Gramantieri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Azienda Ospedaliero, Bologna 40138, Italy
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy
- Department of Pathophysiology and Transplantation, Colorectal Cancer "A. M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milano 20122, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples Federico II, Naples 80131, Italy
| | - Ferran Torres
- Medical Statistics Core Facility, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clinic Barcelona, Barcelona 08036, Spain
- Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Cerdanyola 08193, Spain
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
| | - María Reig
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
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27
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Manjunath M, Swaroop S, Pradhan SS, Rao K R, Mahadeva R, Sivaramakrishnan V, Choudhary B. Integrated Transcriptome and Metabolomic Analysis Reveal Anti-Angiogenic Properties of Disarib, a Novel Bcl2-Specific Inhibitor. Genes (Basel) 2022; 13:genes13071208. [PMID: 35885991 PMCID: PMC9316176 DOI: 10.3390/genes13071208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/25/2022] [Accepted: 06/29/2022] [Indexed: 12/04/2022] Open
Abstract
Transcriptomic profiling of several drugs in cancer cell lines has been utilised to obtain drug-specific signatures and guided combination therapy to combat drug resistance and toxicity. Global metabolomics reflects changes due to altered activity of enzymes, environmental factors, etc. Integrating transcriptomics and metabolomics can provide genotype-phenotype correlation, providing meaningful insights into alterations in gene expression and its outcome to understand differential metabolism and guide therapy. This study uses a multi-omics approach to understand the global gene expression and metabolite changes induced by Disarib, a novel Bcl2-specific inhibitor in the Ehrlich adenocarcinoma (EAC) breast cancer mouse model. RNAseq analysis was performed on EAC mouse tumours treated with Disarib and compared to the controls. The expression of 6 oncogenes and 101 tumour suppressor genes interacting with Bcl2 and Bak were modulated upon Disarib treatment. Cancer hallmark pathways like DNA repair, Cell cycle, angiogenesis, and mitochondrial metabolism were downregulated, and programmed cell death platelet-related pathways were upregulated. Global metabolomic profiling using LC-MS revealed that Oncometabolites like carnitine, oleic acid, glycine, and arginine were elevated in tumour mice compared to normal and were downregulated upon Disarib treatment. Integrated transcriptomic and metabolomic profiles identified arginine metabolism, histidine, and purine metabolism to be altered upon Disarib treatment. Pro-angiogenic metabolites, arginine, palmitic acid, oleic acid, and myristoleic acid were downregulated in Disarib-treated mice. We further validated the effect of Disarib on angiogenesis by qRT-PCR analysis of genes in the VEGF pathway. Disarib treatment led to the downregulation of pro-angiogenic markers. Furthermore, the chorioallantoic membrane assay displayed a reduction in the formation of the number of secondary blood vessels upon Disarib treatment. Disarib reduces tumours by reducing oncometabolite and activating apoptosis and downregulating angiogenesis.
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Affiliation(s)
- Meghana Manjunath
- Institute of Bioinformatics and Applied Biotechnology, Bengaluru 560100, Karnataka, India; (M.M.); (R.R.K.); (R.M.)
- Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Sai Swaroop
- Disease Biology Lab, Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Anantapur 515001, Andhra Pradesh, India; (S.S.); (S.S.P.); (V.S.)
| | - Sai Sanwid Pradhan
- Disease Biology Lab, Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Anantapur 515001, Andhra Pradesh, India; (S.S.); (S.S.P.); (V.S.)
| | - Raksha Rao K
- Institute of Bioinformatics and Applied Biotechnology, Bengaluru 560100, Karnataka, India; (M.M.); (R.R.K.); (R.M.)
| | - Raghunandan Mahadeva
- Institute of Bioinformatics and Applied Biotechnology, Bengaluru 560100, Karnataka, India; (M.M.); (R.R.K.); (R.M.)
| | - Venketesh Sivaramakrishnan
- Disease Biology Lab, Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Anantapur 515001, Andhra Pradesh, India; (S.S.); (S.S.P.); (V.S.)
| | - Bibha Choudhary
- Institute of Bioinformatics and Applied Biotechnology, Bengaluru 560100, Karnataka, India; (M.M.); (R.R.K.); (R.M.)
- Correspondence:
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28
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The use of renin angiotensin aldosterone system inhibitors may be associated with decreased mortality after cancer surgery. Sci Rep 2022; 12:6838. [PMID: 35477724 PMCID: PMC9046295 DOI: 10.1038/s41598-022-10759-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 04/04/2022] [Indexed: 11/10/2022] Open
Abstract
Renin–angiotensin–aldosterone system (RAAS) inhibitors are antihypertensive agents with conflicting results on protective effects against some types of cancer. In light of these controversies, we aimed to study the effects of RAAS inhibitors in patients undergoing cancer surgery. From March 2010 to December 2019, consecutive adult patients with antihypertensive drug prescription at discharge after cancer surgery were enrolled and divided into two groups according to RAAS inhibitors prescription. The primary outcome was 5-year mortality after surgery. Secondary outcomes included mortalities during 3-year and 1-year follow-ups and cancer-specific mortality and recurrence rates during 5-, 3-, and 1-year follow-ups. A total of 19,765 patients were divided into two groups according to RAAS inhibitor prescription at discharge: 8,374 (42.4%) patients in the no RAAS inhibitor group and 11,391 (57.6%) patients in the RAAS inhibitor group. In 5022 pairs of propensity-score matched population, 5-year mortality was significantly lower in the RAAS inhibitor group (11.4% vs. 7.4%, hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.64–0.83, P < 0.001), and 5-year recurrence rate was also lower for the RAAS inhibitor group (5.3% vs. 3.7%, HR 0.82, 95% CI 0.68–0.99, P = 0.04). In our analysis, RAAS inhibitor was associated with decreased 5-year mortality in hypertensive patients who underwent cancer surgery. Prescription of RAAS inhibitor in accordance with current guidelines may be associated with improved mortality after cancer surgery.
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Ni N, Fang X, Mullens DA, Cai JJ, Ivanov I, Bartholin L, Li Q. Transcriptomic Profiling of Gene Expression Associated with Granulosa Cell Tumor Development in a Mouse Model. Cancers (Basel) 2022; 14:2184. [PMID: 35565312 PMCID: PMC9105549 DOI: 10.3390/cancers14092184] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/05/2022] [Accepted: 04/24/2022] [Indexed: 11/16/2022] Open
Abstract
Ovarian granulosa cell tumors (GCTs) are rare sex cord-stromal tumors, accounting for ~5% ovarian tumors. The etiology of GCTs remains poorly defined. Genetically engineered mouse models are potentially valuable for understanding the pathogenesis of GCTs. Mice harboring constitutively active TGFβ signaling (TGFBR1-CA) develop ovarian GCTs that phenocopy several hormonal and molecular characteristics of human GCTs. To determine molecular alterations in the ovary upon TGFβ signaling activation, we performed transcriptomic profiling of gene expression associated with GCT development using ovaries from 1-month-old TGFBR1-CA mice and age-matched controls. RNA-sequencing and bioinformatics analysis coupled with the validation of select target genes revealed dysregulations of multiple cellular events and signaling molecules/pathways. The differentially expressed genes are enriched not only for known GCT-related pathways and tumorigenic events but also for signaling events potentially mediated by neuroactive ligand-receptor interaction, relaxin signaling, insulin signaling, and complements in TGFBR1-CA ovaries. Additionally, a comparative analysis of our data in mice with genes dysregulated in human GCTs or granulosa cells overexpressing a mutant FOXL2, the genetic hallmark of adult GCTs, identified some common genes altered in both conditions. In summary, this study has revealed the molecular signature of ovarian GCTs in a mouse model that harbors the constitutive activation of TGFBR1. The findings may be further exploited to understand the pathogenesis of a class of poorly defined ovarian tumors.
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Affiliation(s)
- Nan Ni
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA; (N.N.); (X.F.); (J.J.C.)
| | - Xin Fang
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA; (N.N.); (X.F.); (J.J.C.)
| | - Destiny A. Mullens
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA; (D.A.M.); (I.I.)
| | - James J. Cai
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA; (N.N.); (X.F.); (J.J.C.)
| | - Ivan Ivanov
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA; (D.A.M.); (I.I.)
| | - Laurent Bartholin
- INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université Lyon 1, F-69000 Lyon, France;
- Centre Léon Bérard, F-69008 Lyon, France
| | - Qinglei Li
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA; (N.N.); (X.F.); (J.J.C.)
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30
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Li PC, Huang RY, Yang YC, Hsieh KP, Yang YH. Prognostic impact of angiotensin-converting enzyme inhibitors and angiotensin receptors blockers in esophageal or gastric cancer patients with hypertension - a real-world study. BMC Cancer 2022; 22:430. [PMID: 35443635 PMCID: PMC9022235 DOI: 10.1186/s12885-022-09513-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 01/18/2022] [Indexed: 11/10/2022] Open
Abstract
Background Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are used in treating cardiovascular diseases. Previous studies indicated that ACEIs/ARBs may benefit cancer patients by inhibiting tumor angiogenesis and proliferation. The effect of ACEIs/ARBs on cancer survival in esophageal and gastric cancer is still unclear. This study is to investigate the association between ACEIs/ARBs usage and esophageal and gastric cancer prognosis. Methods This retrospective cohort study identified esophageal and gastric cancer patients during 2008–2016 from the Taiwan Cancer Registry, and obtained medication usage and follow-up information from the National Health Insurance Research Database and Death Registry. Analysis groups were defined as ACEIs/ARBs user or non-user based on the usage of ACEIs/ARBs within the 6 months after cancer diagnosis. The stabilized inverse probability of treatment weighting using propensity scores was applied to balance covariates between study groups. We also used Kaplan-Meier estimates and Cox regression to compare survival outcome and estimate hazard ratios (HRs). Results We identified 14,463 and 21,483 newly-diagnosed esophageal and gastric cancer patients during 2008–2016. ACEIs/ARBs users were associated with lower risk of cancer-specific mortality, although only significantly in gastric cancer (gastric: adjusted HR = 0.87, 95% CI = 0.78–0.97; esophageal: adjusted HR =0.88, 95% CI = 0.76–1.02). A better survival outcome was observed among patients who received higher cumulative defined daily dose of ACEIs/ARBs. Conclusions We found that using ACEIs/ARBs after cancer diagnosis were associated with lower risk of mortality. Our results add to the knowledge of the benefit of ACEIs/ARBs against mortality in individuals with esophageal/gastric cancer patients with hypertension. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09513-4.
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Affiliation(s)
- Po-Chih Li
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung, Taiwan.,Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ru-Yu Huang
- National Institute of Cancer Research, National Health Research Institutes, No.367, Sheng-Li Rd., North District, Tainan, 70456, Taiwan
| | - Yu-Chien Yang
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung, Taiwan.,Department of Pharmacy, Chi Mei Medical Center, Tainan, Taiwan
| | - Kun-Pin Hsieh
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung, Taiwan. .,Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Yi-Hsin Yang
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung, Taiwan. .,National Institute of Cancer Research, National Health Research Institutes, No.367, Sheng-Li Rd., North District, Tainan, 70456, Taiwan.
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Asgharzadeh F, Mostafapour A, Ebrahimi S, Amerizadeh F, Sabbaghzadeh R, Hassanian SM, Fakhraei M, Farshbaf A, Ferns GA, Giovannetti E, Avan A, Khazaei M. Inhibition of angiotensin pathway via valsartan reduces tumor growth in models of colorectal cancer. Toxicol Appl Pharmacol 2022; 440:115951. [PMID: 35235860 DOI: 10.1016/j.taap.2022.115951] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 02/09/2022] [Accepted: 02/23/2022] [Indexed: 01/05/2023]
Abstract
BACKGROUND Overexpression of the angiotensin-II receptor and renin-angiotensin system (RAS) has been reported in several malignancies, including colorectal-cancer (CRC), indicating its potential value as a therapeutic target. Here we explored the impact of targeting the RAS using an angiotensin II receptor blocker, valsartan, alone and its combination with Fluorouracil (5-FU) in in vitro and in vivo models of CRC. METHODS Anti-proliferative activity of valsartan was evaluated in 2-/3-dimensional in vitro and in vivo CRC mouse models. The anti-migratory effects of this agent was assessed by wound-healing assay, while apoptosis was studied using 4',6-diamidino-2-phenylindole or DAPI staining, and staining with Annexin-V-fluorescein isothiocyanate with analysis using FACS. Gene-expression was determined at mRNA and protein levels. We further evaluated the anti-inflammatory properties of valsartan by histological analysis and the measurement of oxidative/antioxidant markers. Gelatin zymography was used to measure matrix metalloproteinase-2 and -9 activity (MMP-2 and 9). RESULTS Valsartan suppressed CRC cell-growth and synergistically enhanced the anti-tumor-activities of 5-FU by induction of apoptosis, BAX, BCL2, P53 and modulation of the cell cycle. Valsartan inhibited the cell migration by perturbation of MMP2/9. Furthermore, valsartan inhibited tumor-growth, and this was more pronounced when using the valsartan/5-FU combination. The plausible mechanism for this is via the induction of ROS and down-regulation of SOD, thiol/catalase as well as VEGF. Valsartan may protect cells against intestinal fibrosis by modulation of pro-fibrotic and pro-inflammatory factors including interleukins and Col1A1 expression. CONCLUSIONS Our findings demonstrated that targeting RAS pathway using Valsartan interferes with cell-proliferation, induces apoptosis, reduces migration and synergistically interacts with 5-FU, supporting further studies on this new therapeutic approach for colorectal cancer.
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Affiliation(s)
- Fereshteh Asgharzadeh
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Asma Mostafapour
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Safieh Ebrahimi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Forouzan Amerizadeh
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reihaneh Sabbaghzadeh
- Department of Biology, Faculty of Science, Hakim Sabzevari University, Sabzevar 96179-76487, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Fakhraei
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alieh Farshbaf
- Dental Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research center, Mashhad University of Medical Sciences, Mashhad, Iran..
| | - Majid Khazaei
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Venkatanarayana M, Nuchu R, Babu HS. Ultrasound assisted effective synthesis of benzopril based indole derivatives, docking studies: And there in vitro anti-proliferative effects on various cancer cell lines. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2021.132287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Sipahi I. Risk of cancer with angiotensin-receptor blockers increases with increasing cumulative exposure: Meta-regression analysis of randomized trials. PLoS One 2022; 17:e0263461. [PMID: 35235571 PMCID: PMC8890666 DOI: 10.1371/journal.pone.0263461] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 01/19/2022] [Indexed: 12/31/2022] Open
Abstract
Angiotensin-receptor blockers (ARBs) are a class of drugs approved for the treatment of several common conditions, such as hypertension and heart failure. Recently, regulatory agencies have started to identify possibly carcinogenic nitrosamines and azido compounds in a multitude of formulations of several ARBs, resulting in progressive recalls. Furthermore, data from several randomized controlled trials suggested that there is also a clinically increased risk of cancer and specifically lung cancer with ARBs; whereas other trials suggested no increased risk. The purpose of this analysis was to provide additional insight into the ARB-cancer link by examining whether there is a relationship between degree of cumulative exposure to ARBs and risk of cancer in randomized trials. Trial-level data from ARB Trialists Collaboration including 15 randomized controlled trials was extracted and entered into meta-regression analyses. The two co-primary outcomes were the relationship between cumulative exposure to ARBs and risk of all cancers combined and the relationship between cumulative exposure and risk of lung cancer. A total of 74,021 patients were randomized to an ARB resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent). 61,197 patients were randomized to control. There was a highly significant correlation between the degree of cumulative exposure to ARBs and risk of all cancers combined (slope = 0.07 [95% CI 0.03 to 0.11], p<0.001), and also lung cancer (slope = 0.16 [95% CI 0.05 to 0.27], p = 0.003). Accordingly, in trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk of all cancers combined (I2 = 31.4%, RR 1.11 [95% CI 1.03 to 1.19], p = 0.006). There was a statistically significant increase in risk of lung cancers in trials where the cumulative exposure was greater than 2.5 years (I2 = 0%, RR 1.21 [95% CI 1.02 to 1.44], p = 0.03). In trials with lower cumulative exposure to ARBs, there was no increased risk of all cancers combined or lung cancer. Cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme inhibitor treatment or the type of control (i.e. placebo or non-placebo control). Since this is a trial-level analysis. the effects of patient characteristics such as age and smoking status could not be examined due to lack of patient-level data. In conclusion, this analysis, for the first time, reveals that risk of cancer with ARBs (and specifically lung cancer) increases with increasing cumulative exposure to these drugs. The excess risk of cancer with long-term ARB use has public health implications.
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Affiliation(s)
- Ilke Sipahi
- Department of Cardiology, Acibadem University Medical School, Istanbul, Turkey
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Keith SW, Maio V, Arafat HA, Alcusky M, Karagiannis T, Rabinowitz C, Lavu H, Louis DZ. Angiotensin blockade therapy and survival in pancreatic cancer: a population study. BMC Cancer 2022; 22:150. [PMID: 35130875 PMCID: PMC8819908 DOI: 10.1186/s12885-022-09200-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 01/11/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is one of the most aggressive and challenging cancer types to effectively treat, ranking as the fourth-leading cause of cancer death in the United States. We investigated if exposures to angiotensin II receptor blockers (ARBs) or angiotensin I converting enzyme (ACE) inhibitors after PC diagnosis are associated with survival. METHODS PC patients were identified by ICD-9 diagnosis and procedure codes among the 3.7 million adults living in the Emilia-Romagna Region from their administrative health care database containing patient data on demographics, hospital discharges, all-cause mortality, and outpatient pharmacy prescriptions. Cox modeling estimated covariate-adjusted mortality hazard ratios for time-dependent ARB and ACE inhibitor exposures after PC diagnosis. RESULTS 8,158 incident PC patients were identified between 2003 and 2011, among whom 20% had pancreas resection surgery, 36% were diagnosed with metastatic disease, and 7,027 (86%) died by December 2012. Compared to otherwise similar patients, those exposed to ARBs after PC diagnosis experienced 20% lower mortality risk (HR=0.80; 95% CI: 0.72, 0.89). Those exposed to ACE inhibitors during the first three years of survival after PC diagnosis experienced 13% lower mortality risk (HR=0.87; 95% CI: 0.80, 0.94) which attenuated after surviving three years (HR=1.14; 95% CI: 0.90, 1.45). CONCLUSIONS The results of this large population study suggest that exposures to ARBs and ACE inhibitors after PC diagnosis are significantly associated with improved survival. ARBs and ACE inhibitors could be important considerations for treating PC patients, particularly those with the worst prognosis and most limited treatment options. Considering that these common FDA approved drugs are inexpensive to payers and present minimal increased risk of adverse events to patients, there is an urgent need for randomized clinical trials, large simple randomized trials, or pragmatic clinical trials to formally and broadly evaluate the effects of ARBs and ACE inhibitors on survival in PC patients.
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Affiliation(s)
- Scott W Keith
- Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Medical College, Thomas Jefferson University, 130 S 9th St., 17th Floor, 19107, Philadelphia, PA, USA.
| | - Vittorio Maio
- Jefferson College of Population Health, Thomas Jefferson University, 901 Walnut Street, 10th Floor, 19107, Philadelphia, PA, USA.,Asano-Gonnella Center for Research in Medical Education and Health Care, Sidney Kimmel Medical College, Thomas Jefferson University, 1015 Walnut Street, Suite 319, 19107, Philadelphia, PA, USA
| | - Hwyda A Arafat
- Department of Biomedical Sciences, University of New England, 11 Hills Beach Road, 04005, Biddeford, Maine, USA
| | - Matthew Alcusky
- Division of Epidemiology, Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, USA
| | - Thomas Karagiannis
- Jefferson College of Population Health, Thomas Jefferson University, 901 Walnut Street, 10th Floor, 19107, Philadelphia, PA, USA
| | - Carol Rabinowitz
- Asano-Gonnella Center for Research in Medical Education and Health Care, Sidney Kimmel Medical College, Thomas Jefferson University, 1015 Walnut Street, Suite 319, 19107, Philadelphia, PA, USA
| | - Harish Lavu
- Department of Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, 1025 Walnut St., College Bldg., 6th Floor, 19107, Philadelphia, PA, USA
| | - Daniel Z Louis
- Asano-Gonnella Center for Research in Medical Education and Health Care, Sidney Kimmel Medical College, Thomas Jefferson University, 1015 Walnut Street, Suite 319, 19107, Philadelphia, PA, USA
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Asgharzadeh F, Geraylow KR, Khazaei M, Nassiri M, Hassanian SM, Ferns GA, Avan A. Angiotensin-converting Enzyme Inhibitors and Angiotensin Receptor Blockers as Potential Therapeutic Options for Pancreatic Cancer. Curr Cancer Drug Targets 2022; 22:785-795. [PMID: 35585824 DOI: 10.2174/1568009622666220517104411] [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: 10/06/2021] [Revised: 01/27/2022] [Accepted: 02/15/2022] [Indexed: 11/22/2022]
Abstract
The renin-angiotensin system (RAS) has been reported to have a role in carcinogenesis, and therefore it may be of value as a potential therapeutic target in inhibiting tumor growth. It has been shown that inhibition of RAS via angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor (ARBs) inhibitors may have a protective effect against several malignancies. Here, we provide an overview of the potential value of the RAS pathway and targeting via ACE/ARB inhibitors in pancreatic cancer. Whilst the potential role of RAS as a target for the treatment of pancreatic cancer has been reported, the use of candesartan with gemcitabine failed to improve outcomes in pancreatic cancer. Another study of 1-3 years using ARB was found to reduce the risk of pancreatic cancer. In line with these trials, others have demonstrated that the ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer. Prospective trials are warranted to investigate this hypothesis.
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Affiliation(s)
- Fereshteh Asgharzadeh
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Majid Khazaei
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammadreza Nassiri
- Recombinant Proteins Research Group, The Research Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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Li J, Lam ASM, Yau STY, Yiu KKL, Tsoi KKF. Antihypertensive treatments and risks of lung Cancer: a large population-based cohort study in Hong Kong. BMC Cancer 2021; 21:1202. [PMID: 34763668 PMCID: PMC8582182 DOI: 10.1186/s12885-021-08971-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 11/01/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND There is a growing concern that the use of anti-hypertensives may be associated with an increased risk of cancer, but it remains uncertain for the association between anti-hypertensives and lung cancer risk, as well as their interaction with aspirin in chemoprotective effects. METHODS The goal of this study is to assess the association between anti-hypertensives use and the risk of lung cancer, as well as the chemopreventive impacts from the combination usage of aspirin and anti-hypertensives. A retrospective cohort study was conducted based on all the public hospital electronic medical records in Hong Kong. Patients with prescription records of anti-hypertensives (ACEi/ARB, CCB, β-blocker,α-blocker) and/or aspirin were included as the exposure groups. Using the Cox proportional hazards model with inverse probability weighting, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for lung cancer risk from anti-hypertensives usage or combination usage of aspirin with anti-hypertensives. The likelihood ratio test and interaction model were adopted for exploring the interaction effects with aspirin. RESULTS A total of 6592 and 84,116 lung cancer cases were identified from the groups of anti-hypertensives users and anti-hypertensives users with aspirin, respectively. The group of non-aspirin patients who received anti-hypertensives showed a significantly lower risk of lung cancer (HR: 0.63, 95% CI: 0.60-0.66), compared to those without anti-hypertensives. When aspirin and α-blocker were used simultaneously, it could lower the risk of lung cancer significantly (HR: 0.53, 95% CI: 0.34-0.84). Moreover, the lower risk of lung cancer persisted with a longer follow-up period of anti-hypertensives usage. Combination usage with aspirin in the users of ACEi/ARB, CCB, and α-blocker showed significant interaction effects. However, the smoking effect could not be eliminated in this analysis. DISCUSSION Anti-hypertensive treatment was associated with a lower risk of lung cancer, which is associated with the anti-hypertensives exposure period. The potential interaction on the chemopreventive influence from combination usage of α-blocker and aspirin might exist. More corroborations on these findings are needed to focus on the different settings in future studies.
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Affiliation(s)
- Jinhui Li
- JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Amy S M Lam
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Sarah T Y Yau
- JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, Hong Kong
- SH Big Data Decision Analytics Research Centre, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Karen K L Yiu
- SH Big Data Decision Analytics Research Centre, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Kelvin K F Tsoi
- JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, Hong Kong.
- SH Big Data Decision Analytics Research Centre, The Chinese University of Hong Kong, Shatin, Hong Kong.
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Harewood R, Disney R, Kinross J, von Wagner C, Cross AJ. Medication use and risk of proximal colon cancer: a systematic review of prospective studies with narrative synthesis and meta-analysis. Cancer Causes Control 2021; 32:1047-1061. [PMID: 34224060 PMCID: PMC8417019 DOI: 10.1007/s10552-021-01472-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 06/21/2021] [Indexed: 12/12/2022]
Abstract
PURPOSE Evidence of differences in the etiology of, and poorer survival from, proximal colon compared to the distal colorectum, necessitates research into its risk factors. This systematic review summarizes the evidence on medication use and proximal colon cancer risk. METHODS MEDLINE and EMBASE were searched for prospective studies investigating nine medication groups, namely non-steroidal anti-inflammatory drugs (NSAIDs), exogenous hormones, i.e., hormone replacement therapy (HRT) or oral contraceptives (OCs), statins, proton pump inhibitors, anti-hypertensives, metformin (an antidiabetic), antidiarrheals or laxatives, and the risk of proximal colon cancer. Narrative synthesis and meta-analyses, using random effects models to estimate risk ratios (RRs) and 95% confidence intervals (CIs), were conducted. RESULTS Twenty nine publications investigating NSAIDs (n = 13), exogenous hormones [HRT (n = 9) or OCs (n = 4)] statins (n = 5), anti-hypertensives (n = 1), and metformin (n = 1) were included. Summary RRs reported a protective effect of aspirin use (RR 0.80, 95% CI 0.73-0.89) but no associations between HRT (RR 0.92, 95% CI 0.83-1.02), OC (RR 1.06, 95% CI 0.98-1.14) or statin use (RR 0.94, 95% CI 0.67-1.31), and proximal colon cancer incidence compared to never/non-use. One study on metformin and one on anti-hypertensives reported no association. Sources of between-study heterogeneity included study design, period of exposure ascertainment, exposure source, and exposure comparison, but this exploration was hindered by the small numbers of studies. CONCLUSION Despite some studies on NSAID or HRT use, evidence on the impact of a range of medications on proximal colon cancer risk is limited. This highlights the need for more research to inform chemoprevention strategies.
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Affiliation(s)
- Rhea Harewood
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
- Cancer Screening and Prevention Research Group (CSPRG), Department of Surgery and Cancer, Imperial College London, London, UK.
| | - Ruth Disney
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Cancer Screening and Prevention Research Group (CSPRG), Department of Surgery and Cancer, Imperial College London, London, UK
| | - James Kinross
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Christian von Wagner
- Research Department of Behavioural Science and Health, University College London, London, UK
| | - Amanda J Cross
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Cancer Screening and Prevention Research Group (CSPRG), Department of Surgery and Cancer, Imperial College London, London, UK
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Jaworska K, Koper M, Ufnal M. Gut microbiota and renin-angiotensin system: a complex interplay at local and systemic levels. Am J Physiol Gastrointest Liver Physiol 2021; 321:G355-G366. [PMID: 34405730 PMCID: PMC8486428 DOI: 10.1152/ajpgi.00099.2021] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Gut microbiota is a potent biological modulator of many physiological and pathological states. The renin-angiotensin system (RAS), including the local gastrointestinal RAS (GI RAS), emerges as a potential mediator of microbiota-related effects. The RAS is involved in cardiovascular system homeostasis, water-electrolyte balance, intestinal absorption, glycemic control, inflammation, carcinogenesis, and aging-related processes. Ample evidence suggests a bidirectional interaction between the microbiome and RAS. On the one hand, gut bacteria and their metabolites may modulate GI and systemic RAS. On the other hand, changes in the intestinal habitat caused by alterations in RAS may shape microbiota metabolic activity and composition. Notably, the pharmacodynamic effects of the RAS-targeted therapies may be in part mediated by the intestinal RAS and changes in the microbiome. This review summarizes studies on gut microbiota and RAS physiology. Expanding the research on this topic may lay the foundation for new therapeutic paradigms in gastrointestinal diseases and multiple systemic disorders.
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Affiliation(s)
- Kinga Jaworska
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Mateusz Koper
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Marcin Ufnal
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
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Helgeson SA, Waddle MR, Burnside RC, Debella YT, Lee AS, Burger CD, Li Z, Johnson PW, Patel NM. Association between Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and Lung Cancer. South Med J 2021; 114:607-613. [PMID: 34480196 DOI: 10.14423/smj.0000000000001293] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVES Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are the most commonly prescribed antihypertensives, with prior studies identifying a possible association between long-term use and increased rates of lung cancer. This study evaluated this potential association in a large population using propensity matching. METHODS This was a population-based cohort study in a large healthcare system in three regions of the United States. Pairwise propensity score matching was performed using demographics and comorbidities. All of the adult patients in the healthcare system from January 1, 2000 to April 30, 2018 with at least 1 year of follow-up were included. RESULTS In total, 3,253,811 patients with a median age of 59 (range 18-103) years were included. The ACEI group had a higher freedom from lung cancer versus controls at 15 years (98.47%, 95% confidence interval [CI] 98.41-98.54) versus 98.26%, (95% CI 98.20-98.33), whereas ARBs had similar rates versus controls at all time points. For patients diagnosed as having lung cancer, median all-cause survival was significantly higher in the ACEI (34.7 months, 95% CI 32.8-36.6) and ARB (30.9 months, 95% CI 28.1-33.8) groups than the control group (20.6 months, 95% CI 20.1-21.1). CONCLUSIONS This study showed lower rates of lung cancer with ACEI use and no difference in risk with ARBs. In addition, use of these medications was found to be associated with increased survival in those diagnosed as having lung cancer. This study supports the continued use of these medications without concern for increasing the risk of lung cancer.
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Affiliation(s)
- Scott A Helgeson
- From the Departments of Pulmonary Medicine, Radiation Oncology, and Statistics, Mayo Clinic, Jacksonville, Florida
| | - Mark R Waddle
- From the Departments of Pulmonary Medicine, Radiation Oncology, and Statistics, Mayo Clinic, Jacksonville, Florida
| | - Rebecca C Burnside
- From the Departments of Pulmonary Medicine, Radiation Oncology, and Statistics, Mayo Clinic, Jacksonville, Florida
| | - Yalew T Debella
- From the Departments of Pulmonary Medicine, Radiation Oncology, and Statistics, Mayo Clinic, Jacksonville, Florida
| | - Augustine S Lee
- From the Departments of Pulmonary Medicine, Radiation Oncology, and Statistics, Mayo Clinic, Jacksonville, Florida
| | - Charles D Burger
- From the Departments of Pulmonary Medicine, Radiation Oncology, and Statistics, Mayo Clinic, Jacksonville, Florida
| | - Zhuo Li
- From the Departments of Pulmonary Medicine, Radiation Oncology, and Statistics, Mayo Clinic, Jacksonville, Florida
| | - Patrick W Johnson
- From the Departments of Pulmonary Medicine, Radiation Oncology, and Statistics, Mayo Clinic, Jacksonville, Florida
| | - Neal M Patel
- From the Departments of Pulmonary Medicine, Radiation Oncology, and Statistics, Mayo Clinic, Jacksonville, Florida
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Shafiee S, Cegolon L, Khafaei M, Gholami N, Zhao S, Khalesi N, Moosavian H, Fathi S, Izadi M, Ghadian A, Javanbakht M, Javanbakht A, Akhavan-Sigari R. Gastrointestinal cancers, ACE-2/TMPRSS2 expression and susceptibility to COVID-19. Cancer Cell Int 2021; 21:431. [PMID: 34399734 PMCID: PMC8365127 DOI: 10.1186/s12935-021-02129-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 07/30/2021] [Indexed: 12/22/2022] Open
Abstract
Recent studies on the pathophysiology of COVID-19 are indicating that the Angiotensin convertase enzyme 2 (ACE-2) and transmembrane serine protease 2 (TMPRSS2) can act as a major component in the fusion of SARS-Cov-2 with target cells. It has also been observed that the expression of ACE-2 and TMPRSS2 can be altered in malignancies. Shedding light on this matter could be crucial since the COVID-19 pandemic interfered with many gastrointestinal cancer screening programs. Herein we discuss the possibility of severe forms of COVID-19 in patients with gastrointestinal cancers due to the gastrointestinal entry route of SARS-CoV-2 into the human body. The disruption of cancer screening programs caused by the current COVID-19 pandemic could therefore have massive negative health impact on patients affected by gastrointestinal malignancies.
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Affiliation(s)
- Sepehr Shafiee
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Luca Cegolon
- Public Health Department, Local Health Unit N.2 "Marca Trevigiana", 31100, Treviso, Italy
| | - Mostafa Khafaei
- Human Genetics Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Nasrin Gholami
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shi Zhao
- JC School of Public Health and Primary Care, Chinese University of Hong Kong, Hong Kong, China
| | - Nasrin Khalesi
- Department of Pediatrics, Iran University of Medical Sciences, Tehran, Iran
| | - Hamidreza Moosavian
- Department of Clinical Pathology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Saeid Fathi
- Department of Parasite Vaccine Research and Production, Razi Vaccine and Serum Research Institute, Agriculture Research, Education and Extension Organization (AREEO), Karaj, Iran
| | - Morteza Izadi
- Health Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Alireza Ghadian
- Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mohammad Javanbakht
- Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Abstract
Cancer and cardiovascular diseases, including heart failure (HF), are the main causes of death in Western countries. Several anticancer drugs and radiotherapy have adverse effects on the cardiovascular system, promoting left ventricular dysfunction and ultimately HF. Nonetheless, the relationship between cancer and HF is likely not unidirectional. Indeed, cancer and HF share common risk factors, and both have a bidirectional relationship with systemic inflammation, metabolic disturbances, and neurohormonal and immune activation. Few studies have assessed the impact of untreated cancer on the heart. The presence of an active cancer has been associated with elevated cardiac biomarkers, an initial impairment of left ventricular structure and function, autonomic dysfunction, and reduced exercise tolerance. In turn, these conditions might increase the risk of cardiac damage from chemotherapy and radiotherapy. HF drugs such as beta-blockers or inhibitors of the renin–angiotensin–aldosterone system might exert a protective effect on the heart even before the start of cancer therapies. In this review, we recapitulate the evidence of cardiac involvement in cancer patients naïve from chemotherapy and radiotherapy and no history of cardiac disease. We also focus on the perspectives for an early diagnosis and treatment to prevent the progression to cardiac dysfunction and clinical HF, and the potential benefits of cardioactive drugs on cancer progression.
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Avsar T, Yigit BN, Turan G, Altunsu D, Calis S, Kurt B, Kilic T, Yavuz Ergun M, Durdagi S, Acar M. Development of imidazolone based angiotensin II receptor type I inhibitor small molecule as a chemotherapeutic agent for cell cycle inhibition. ALL LIFE 2021. [DOI: 10.1080/26895293.2021.1954098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Affiliation(s)
- Timucin Avsar
- Department of Medical Biology, School of Medicine, Bahcesehir University, Istanbul, Turkey
- Neuroscience Program, Health Sciences Institute, Bahcesehir University, Istanbul, Turkey
- Neuroscience Laboratory, Health Sciences Institute, Bahcesehir University, Istanbul, Turkey
| | - Berfu Nur Yigit
- Neuroscience Program, Health Sciences Institute, Bahcesehir University, Istanbul, Turkey
- Neuroscience Laboratory, Health Sciences Institute, Bahcesehir University, Istanbul, Turkey
| | - Gizem Turan
- Neuroscience Program, Health Sciences Institute, Bahcesehir University, Istanbul, Turkey
- Neuroscience Laboratory, Health Sciences Institute, Bahcesehir University, Istanbul, Turkey
| | - Deniz Altunsu
- Neuroscience Program, Health Sciences Institute, Bahcesehir University, Istanbul, Turkey
- Neuroscience Laboratory, Health Sciences Institute, Bahcesehir University, Istanbul, Turkey
| | - Seyma Calis
- Neuroscience Laboratory, Health Sciences Institute, Bahcesehir University, Istanbul, Turkey
- Graduate School of Science, Engineering and Technology, Molecular Biology, Genetics and Biotechnology Graduate Program, Istanbul Technical University, Istanbul, Turkey
| | - Bahar Kurt
- Neuroscience Laboratory, Health Sciences Institute, Bahcesehir University, Istanbul, Turkey
| | - Turker Kilic
- Neuroscience Program, Health Sciences Institute, Bahcesehir University, Istanbul, Turkey
- Neuroscience Laboratory, Health Sciences Institute, Bahcesehir University, Istanbul, Turkey
- Department of Neurosurgery, School of Medicine, Bahcesehir University, Istanbul, Turkey
| | - M. Yavuz Ergun
- Department of Chemistry, Dokuz Eylul University, Izmir, Turkey
| | - Serdar Durdagi
- Neuroscience Program, Health Sciences Institute, Bahcesehir University, Istanbul, Turkey
- Department of Biophysics, Computational Biology and Molecular Simulations Laboratory, School of Medicine, Bahcesehir University Istanbul, Turkey
| | - Melih Acar
- Department of Medical Biology, School of Medicine, Bahcesehir University, Istanbul, Turkey
- Neuroscience Laboratory, Health Sciences Institute, Bahcesehir University, Istanbul, Turkey
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Iftikhar A, Islam M, Shepherd S, Jones S, Ellis I. Is RAS the Link Between COVID-19 and Increased Stress in Head and Neck Cancer Patients? Front Cell Dev Biol 2021; 9:714999. [PMID: 34336866 PMCID: PMC8320172 DOI: 10.3389/fcell.2021.714999] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 06/25/2021] [Indexed: 01/04/2023] Open
Abstract
The COVID-19 pandemic emerged as a largely unexplained outbreak of pneumonia cases, in Wuhan City, China and rapidly spread across the world. By 11th March 2020, WHO declared it as a global pandemic. The resulting restrictions, to contain its spread, demanded a momentous change in the lifestyle of the general population as well as cancer patients. This augmented negative effects on the mental health of patients with head and neck cancer (HNC), who already battle with the stress of cancer diagnosis and treatment. The causative agent of COVID-19, SARS-CoV2, gains entry through the Angiotensin converting enzyme 2 (ACE2) receptor, which is a component of the Renin Angiotensin System (RAS). RAS has been shown to influence cancer and stress such that it can have progressive and suppressive effects on both. This review provides an overview of SARS-CoV2, looks at how the RAS provides a mechanistic link between stress, cancer and COVID-19 and the probable activation of the RAS axis that increase stress (anxiogenic) and tumor progression (tumorigenic), when ACE2 is hijacked by SARS-CoV2. The mental health crises brought about by this pandemic have been highlighted in many studies. The emerging links between cancer and stress make it more important than ever before to assess the stress burden of cancer patients and expand the strategies for its management.
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Affiliation(s)
| | | | | | | | - Ian Ellis
- Unit of Cell and Molecular Biology, The Dental School, University of Dundee, Dundee, United Kingdom
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Mandal S, Chakrabarty D, Bhattacharya A, Paul J, Haldar S, Pal K. miRNA regulation of G protein-coupled receptor mediated angiogenic pathways in cancer. THE NUCLEUS 2021. [DOI: 10.1007/s13237-021-00365-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Al-Benna S. Angiotensin-converting enzyme 2 gene expression in human male urological tissues: implications for pathogenesis and virus transmission pathways. AFRICAN JOURNAL OF UROLOGY 2021; 27:89. [PMID: 34230799 PMCID: PMC8248760 DOI: 10.1186/s12301-021-00192-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 12/06/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection occurs through binding and internalization of the viral spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell membrane. Pathological changes are caused by damage and failure of vital organs that express high levels of ACE2, including the lungs, the heart and the kidneys. The aim of this study was to investigate ACE2 gene expression in the human male urogenital tract using a public database. METHODS A search of transcriptomic datasets from a database to investigate ACE2 gene expression in human urogenital tract tissue. RESULTS The gene expression profile demonstrated that ACE2 gene expression was higher in human kidney cortex and testis than human lung tissue. The gene expression profile demonstrated that ACE2 gene expression in the human bladder and prostate was comparable to human lung tissue. CONCLUSIONS Male urogenital tissues are directly susceptible to SARS-CoV-2 infection through the expression of ACE2. Moreover, the SARS-Cov-2/ACE2 interaction may disturb the male genital and reproductive functions.
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Affiliation(s)
- Sammy Al-Benna
- Department of Surgical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Francie van Zijl Drive, PO Box 241, Cape Town, 8000 South Africa
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Banerjee J, Gupta A, Agnihotri V, Pradhan R, Kandel R, Upadhyay AD, Dwivedi S, Kumar L, Dey S, Dey AB. Lung cancer in the older population:Interactive effects of angiotensin converting enzyme gene polymorphism (rs 4340 ID) and tobacco addiction in risk assessment. Indian J Cancer 2021; 0:318894. [PMID: 34380830 DOI: 10.4103/ijc.ijc_1082_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND rs4340ID polymorphism of angiotensin-converting enzyme (ACE) correlates with serum ACE levels in many known cancers. This study analyzed ACE rs4340 ID polymorphism in lung cancer (LC) in older patients of North India and correlated it with addiction status. METHODS The study enrolled all subjects aged 60 years and above with 154 LC and 205 healthy controls. Genotyping was done by polymerase chain reaction (PCR) and validated by sequencing of 10% of the sample. Statistical analysis was done by SPSS Statistics 21. RESULTS Genotype II was observed to have a significant 2.21-fold increased risk of LC as compared to the DD genotype and 3.43-folds enhanced risk with interaction of I allele with tobacco consumption habits as compared to D allele in LC was seen. CONCLUSION The risk of LC was higher with II genotype as compared to DD genotype. Interactive effect showed that I allele with tobacco habits may increase the risk of LC.
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Affiliation(s)
- Joyita Banerjee
- Department of Geriatric Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Abhishek Gupta
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
| | - Vertica Agnihotri
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
| | - Rashmita Pradhan
- Department of Geriatric Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Ramesh Kandel
- Department of Geriatric Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Ashish D Upadhyay
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
| | - Sadanand Dwivedi
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
| | - Lalit Kumar
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Sharmistha Dey
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
| | - Aparajit B Dey
- Department of Geriatric Medicine, All India Institute of Medical Sciences, New Delhi, India
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Rao VU, Reeves DJ, Chugh AR, O'Quinn R, Fradley MG, Raghavendra M, Dent S, Barac A, Lenihan D. Clinical Approach to Cardiovascular Toxicity of Oral Antineoplastic Agents: JACC State-of-the-Art Review. J Am Coll Cardiol 2021; 77:2693-2716. [PMID: 34045027 DOI: 10.1016/j.jacc.2021.04.009] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/30/2021] [Accepted: 04/06/2021] [Indexed: 12/14/2022]
Abstract
Precision medicine has ushered in a new era of targeted treatments for numerous malignancies, leading to improvements in overall survival. Unlike traditional chemotherapy, many molecular targeted antineoplastic agents are available in oral formulation, leading to enhanced patient convenience and a perception of reduced risk of adverse effects. Although oral antineoplastic agents are generally well-tolerated, cardiovascular toxicities are being reported with increasing frequency in part due to U.S. Food and Drug Administration and manufacturer recommended cardiac monitoring. Monitoring strategies have focused on left ventricular dysfunction, hypertension, and QT prolongation/arrhythmias. Given the rapid pace of development and availability of new oral antineoplastic agents, the purpose of this review is to provide clinicians with an up-to-date practical approach to monitoring and management of cardiovascular toxicities with the aim of improving overall outcomes for patients with cancer.
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Affiliation(s)
- Vijay U Rao
- Franciscan Cardio-Oncology Center, Indiana Heart Physicians, Franciscan Health, Indianapolis, Indiana, USA.
| | - David J Reeves
- Division of Oncology, Franciscan Health and Butler University College of Pharmacy and Health Sciences, Indianapolis, Indiana, USA
| | - Atul R Chugh
- Franciscan Cardio-Oncology Center, Indiana Heart Physicians, Franciscan Health, Indianapolis, Indiana, USA
| | - Rupal O'Quinn
- Cardio-Oncology Center of Excellence, Division of Cardiology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Michael G Fradley
- Cardio-Oncology Center of Excellence, Division of Cardiology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Meghana Raghavendra
- Franciscan Cardio-Oncology Center, Oncology and Hematology Specialists, Franciscan Health, Indianapolis, Indiana, USA
| | - Susan Dent
- Duke Cancer Institute, Duke University, Durham, North Carolina, USA
| | - Ana Barac
- Medstar Heart and Vascular Institute, Georgetown University, Washington, DC, USA
| | - Daniel Lenihan
- Cardio-Oncology Center of Excellence, Washington University in St. Louis, St. Louis, Missouri, USA
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Ranjit A, Khajehpour S, Aghazadeh-Habashi A. Update on Angiotensin II Subtype 2 Receptor: Focus on Peptide and Nonpeptide Agonists. Mol Pharmacol 2021; 99:469-487. [PMID: 33795351 DOI: 10.1124/molpharm.121.000236] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 03/12/2021] [Indexed: 11/22/2022] Open
Abstract
Angiotensin II (Ang II) is the most dominant effector component of the renin-angiotensin system (RAS) that generally acts through binding to two main classes of G protein-coupled receptors, namely Ang II subtype 1 receptor (AT1R) and angiotensin II subtype 2 receptor (AT2R). Despite some controversial reports, the activation of AT2R generally antagonizes the effects of Ang II binding on AT1R. Studying AT2R signaling, function, and its specific ligands in cell culture or animal studies has confirmed its beneficial effects throughout the body. These characteristics classify AT2R as part of the protective arm of the RAS that, along with functions of Ang (1-7) through Mas receptor signaling, modulates the harmful effects of Ang II on AT1R in the activated classic arm of the RAS. Although Ang II is the primary ligand for AT2R, we have summarized other natural or synthetic peptide and nonpeptide agonists with critical evaluation of their structure, mechanism of action, and biologic activity. SIGNIFICANCE STATEMENT: AT2R is one of the main components of the RAS and has a significant prospective for mediating the beneficial action of the RAS through its protective arm on the body's homeostasis. Targeting AT2R offers substantial clinical application possibilities for modulating various pathological conditions. This review provided concise information regarding the AT2R peptide and nonpeptide agonists and their potential clinical applications for various diseases.
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Affiliation(s)
- Arina Ranjit
- College of Pharmacy, Idaho State University, Pocatello, Idaho, USA
| | - Sana Khajehpour
- College of Pharmacy, Idaho State University, Pocatello, Idaho, USA
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de Miranda FS, Guimarães JPT, Menikdiwela KR, Mabry B, Dhakal R, Rahman RL, Moussa H, Moustaid-Moussa N. Breast cancer and the renin-angiotensin system (RAS): Therapeutic approaches and related metabolic diseases. Mol Cell Endocrinol 2021; 528:111245. [PMID: 33753205 DOI: 10.1016/j.mce.2021.111245] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 03/09/2021] [Accepted: 03/15/2021] [Indexed: 12/12/2022]
Abstract
The Renin-Angiotensin System (RAS) is classically recognized for regulating blood pressure and fluid balance. Recently, this role has extended to other areas including inflammation, obesity, diabetes, as well as breast cancer. RAS components are expressed in normal and cancerous breast tissues, and downregulation of RAS inhibits metastasis, proliferation, angiogenesis, and desmoplasia in the tumor microenvironment. Therefore, RAS inhibitors (Angiotensin receptor blockers, ARBs, or angiotensin converting enzyme inhibitors, ACE-I) may be beneficial as preventive adjuvant therapies to thwart breast cancer development and improve outcomes, respectively. Given the beneficial effects of RAS inhibitors in metabolic diseases, which often co-exist in breast cancer patients, combining RAS inhibitors with other breast cancer therapies may enhance the effectiveness of current treatments. This review scrutinizes above associations, to advance our understanding of the role of RAS in breast cancer and its potential for repurposing of RAS inhibitors to improve the therapeutic approach for breast cancer patients.
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Affiliation(s)
- Flávia Sardela de Miranda
- Laboratory of Nutrigenomics, Inflammation and Obesity Research, Department of Nutritional Sciences, Texas Tech University (TTU), Lubbock, TX, USA; Obesity Research Institute, Texas Tech University, Lubbock, TX, USA
| | - João Pedro Tôrres Guimarães
- Laboratory of Nutrigenomics, Inflammation and Obesity Research, Department of Nutritional Sciences, Texas Tech University (TTU), Lubbock, TX, USA; Obesity Research Institute, Texas Tech University, Lubbock, TX, USA; Laboratory of Immunopharmacology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo (ICB/USP), São Paulo, SP, Brazil; Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo (FCF/USP), São Paulo, SP, Brazil
| | - Kalhara R Menikdiwela
- Laboratory of Nutrigenomics, Inflammation and Obesity Research, Department of Nutritional Sciences, Texas Tech University (TTU), Lubbock, TX, USA; Obesity Research Institute, Texas Tech University, Lubbock, TX, USA
| | - Brennan Mabry
- Laboratory of Nutrigenomics, Inflammation and Obesity Research, Department of Nutritional Sciences, Texas Tech University (TTU), Lubbock, TX, USA
| | - Rabin Dhakal
- Department of Mechanical Engineering, Texas Tech University (TTU), Lubbock, TX, USA
| | - Rakhshanda Layeequr Rahman
- Department of Surgery, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Hanna Moussa
- Obesity Research Institute, Texas Tech University, Lubbock, TX, USA; Department of Mechanical Engineering, Texas Tech University (TTU), Lubbock, TX, USA
| | - Naima Moustaid-Moussa
- Laboratory of Nutrigenomics, Inflammation and Obesity Research, Department of Nutritional Sciences, Texas Tech University (TTU), Lubbock, TX, USA; Obesity Research Institute, Texas Tech University, Lubbock, TX, USA.
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50
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Wang W, He Q, Zhang H, Zhuang C, Wang Q, Li C, Sun R, Fan X, Yu J. A narrative review on the interaction between genes and the treatment of hypertension and breast cancer. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:894. [PMID: 34164528 PMCID: PMC8184430 DOI: 10.21037/atm-21-2133] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Objective The aim to discuss the close relationship between the common biological mechanisms of breast cancer and hypertension, inflammation and oxidative stress, breast cancer gene mutations breast cancer susceptibility gene (BRCA), G protein-coupled receptor kinase (GRK4), etc. and breast cancer treatment includes chemotherapy, Endocrine therapy, Targeted therapy and anti-angiogenesis drugs. In anti-angiogenesis drugs focusing on the mechanism of tyrosine kinase inhibitors (TKI) that may activate the rhoa/rock pathway to cause hypertension, as well as the relationship between breast cancer and antihypertensive drugs includes angiotensin-converting enzyme inhibitors (ACEIs), Calcium channel blockers (CCBs) and β-blockers (BBs)will be explored. Background Cardiovascular diseases (CVD) and tumors are the two major types of diseases with the highest mortality rates, while hypertension accounts for the largest proportion of CVDs. A large number of the same or similar risk factors are shared between hypertension and tumors, and they influence each other. Many patients, particularly elderly patients, often present with the coexistence of the two diseases. As medical advances have enabled clinicians to cure tumors, many patients with cancer live longer, leading to a gradual increase in the incidence of CVDs, including hypertension. With the second highest incidence among tumors, breast cancer has gradually attracted widespread attention and has been the topic of numerous studies. Studies have confirmed that CVD is one of the causes of death in elderly patients with breast cancer. Methods Publications from 1985 to 2020 were retrieved from the Web Of Science, Cochrane Library, PubMed, EMBASE and MEDLINE database. We used a mix of MeSH and keywords. Conclusions Hypertension and cancer may share a common mechanism. The screening and risk assessment of breast cancer in patients with hypertension must be strengthened. Breast cancer cardiology is the interdisciplinary study of oncology and cardiology, and in-depth research in this field may result in long-term improvements in the survival and prognosis of patients with both clinical hypertension and breast cancer.
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Affiliation(s)
- Wenjuan Wang
- Department of Hypertension Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Qingjian He
- Department of Breast and Thyroid Surgery, Zhoushan Hospital of Zhejiang Province, Zhoushan, China
| | - Haodong Zhang
- Department of Hypertension Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Chenchen Zhuang
- Department of Hypertension Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Qiongying Wang
- Department of Hypertension Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Caie Li
- Department of Hypertension Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Runmin Sun
- Department of Hypertension Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Xin Fan
- Department of Hypertension Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Jing Yu
- Department of Hypertension Center, Lanzhou University Second Hospital, Lanzhou, China
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