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Zmaili M, Alzubi J, Alkhayyat M, Albakri A, Alkhalaileh F, Longinow J, Moudgil R. Cancer and Cardiovascular Disease: The Conjoined Twins. Cancers (Basel) 2024; 16:1450. [PMID: 38672532 PMCID: PMC11048405 DOI: 10.3390/cancers16081450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 03/21/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
Cancer and cardiovascular disease are the two most common causes of death worldwide. As the fields of cardiovascular medicine and oncology continue to expand, the area of overlap is becoming more prominent demanding dedicated attention and individualized patient care. We have come to realize that both fields are inextricably intertwined in several aspects, so much so that the mere presence of one, with its resultant downstream implications, has an impact on the other. Nonetheless, cardiovascular disease and cancer are generally approached independently. The focus that is granted to the predominant pathological entity (either cardiovascular disease or cancer), does not allow for optimal medical care for the other. As a result, ample opportunities for improvement in overall health care are being overlooked. Herein, we hope to shed light on the interconnected relationship between cardiovascular disease and cancer and uncover some of the unintentionally neglected intricacies of common cardiovascular therapeutics from an oncologic standpoint.
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Affiliation(s)
- Mohammad Zmaili
- Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA;
| | - Jafar Alzubi
- Department of Medicine, Division of Cardiology, Einstein Medical Center, Philadelphia, PA 19141, USA
| | - Motasem Alkhayyat
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Almaza Albakri
- Jordanian Royal Medical Services, Department of Internal Medicine, King Abdullah II Ben Al-Hussein Street, Amman 11855, Jordan
| | - Feras Alkhalaileh
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Joshua Longinow
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Rohit Moudgil
- Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA;
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
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Sayour NV, Paál ÁM, Ameri P, Meijers WC, Minotti G, Andreadou I, Lombardo A, Camilli M, Drexel H, Grove EL, Dan GA, Ivanescu A, Semb AG, Savarese G, Dobrev D, Crea F, Kaski JC, de Boer RA, Ferdinandy P, Varga ZV. Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence. Eur Heart J 2024; 45:1224-1240. [PMID: 38441940 PMCID: PMC11023004 DOI: 10.1093/eurheartj/ehae105] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 01/08/2024] [Accepted: 02/07/2024] [Indexed: 04/08/2024] Open
Abstract
Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.
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Affiliation(s)
- Nabil V Sayour
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1085 Budapest, Üllői út 26, Hungary
- HCEMM-SU Cardiometabolic Immunology Research Group, H-1089 Budapest, Nagyvárad tér 4, Hungary
- MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, H-1089 Budapest, Nagyvárad tér 4, Hungary
| | - Ágnes M Paál
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1085 Budapest, Üllői út 26, Hungary
| | - Pietro Ameri
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, Italian IRCCS Cardiology Network, Genova, Italy
- Department of Internal Medicine, University of Genova, Genova, Italy
| | - Wouter C Meijers
- Department of Cardiology, Thorax Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Giorgio Minotti
- University Campus Bio-Medico, Via Álvaro del Portillo, 21, 00128 Rome, Italy
| | - Ioanna Andreadou
- Laboratory of Pharmacology, School of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Antonella Lombardo
- Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Massimiliano Camilli
- Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Heinz Drexel
- Vorarlberg Institute for Vascular Investigation & Treatment (VIVIT), Carinagasse 47, A-6800 Feldkirch, Austria
| | - Erik Lerkevang Grove
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Gheorghe Andrei Dan
- Carol Davila University of Medicine and Pharmacy, Colentina University Hospital, Bucharest, Romania
- Cardiology Department, Colentina Clinical Hospital, Bucharest, Romania
| | - Andreea Ivanescu
- Carol Davila University of Medicine and Pharmacy, Colentina University Hospital, Bucharest, Romania
- Cardiology Department, Colentina Clinical Hospital, Bucharest, Romania
| | - Anne Grete Semb
- Division of Research and Innovation, REMEDY-Centre for Treatment of Rheumatic and Musculoskeletal Diseases, Diakonhjemmet Hospital, Oslo, Norway
| | - Gianluigi Savarese
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- Heart and Vascular and Neuro Theme, Karolinska University Hospital, Stockholm, Sweden
| | - Dobromir Dobrev
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany
- Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, QC, Canada
- Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA
| | - Filippo Crea
- Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Juan-Carlos Kaski
- Molecular and Clinical Sciences Research Institute, St. George’s University of London, London, United Kingdom
| | - Rudolf A de Boer
- Department of Cardiology, Thorax Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1085 Budapest, Üllői út 26, Hungary
- Pharmahungary Group, Szeged, Hungary
- MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Zoltán V Varga
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1085 Budapest, Üllői út 26, Hungary
- HCEMM-SU Cardiometabolic Immunology Research Group, H-1089 Budapest, Nagyvárad tér 4, Hungary
- MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, H-1089 Budapest, Nagyvárad tér 4, Hungary
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Sun J, Zhang C, Su X, Zhou H, Zhou S, Jiang M, Fang B. Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy. J Orthop Surg Res 2024; 19:147. [PMID: 38373964 PMCID: PMC10875773 DOI: 10.1186/s13018-024-04627-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 02/14/2024] [Indexed: 02/21/2024] Open
Abstract
PURPOSE Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy. METHODS We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8+ T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism. RESULTS Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays. CONCLUSION Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future.
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Affiliation(s)
- Jianwen Sun
- Department of Orthopaedics, The First Affiliated Hospital of Jishou University, The People's Hospital of Xiangxi Autonomous Prefecture, Jishou, China
| | | | - Xinhao Su
- Department of Jishou University, Jishou, China
| | - Haoyun Zhou
- Department of Medicine, Taizhou University, Zhejiang, China
| | - Siyun Zhou
- Department of Medicine, Taizhou University, Zhejiang, China
| | - Minjie Jiang
- Department of Medicine, Taizhou University, Zhejiang, China
| | - Binbo Fang
- Department of Medicine, Taizhou University, Zhejiang, China.
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Pillai U J, Ray A, Maan M, Dutta M. Repurposing drugs targeting metabolic diseases for cancer therapeutics. Drug Discov Today 2023; 28:103684. [PMID: 37379903 DOI: 10.1016/j.drudis.2023.103684] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 06/01/2023] [Accepted: 06/18/2023] [Indexed: 06/30/2023]
Abstract
Hurdles in the identification of new drugs for cancer treatment have made drug repurposing an increasingly appealing alternative. The approach involves the use of old drugs for new therapeutic purposes. It is cost-effective and facilitates rapid clinical translation. Given that cancer is also considered a metabolic disease, drugs for metabolic disorders are being actively repurposed for cancer therapeutics. In this review, we discuss the repurposing of such drugs approved for two major metabolic diseases, diabetes and cardiovascular disease (CVD), which have shown potential as anti-cancer treatment. We also highlight the current understanding of the cancer signaling pathways that these drugs target.
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Affiliation(s)
- Jisha Pillai U
- Department of Biotechnology, BITS Pilani, Dubai Campus, Academic City, Dubai, UAE
| | - Anindita Ray
- Department of Biotechnology, BITS Pilani, Dubai Campus, Academic City, Dubai, UAE
| | - Meenu Maan
- Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai, UAE; New York University-Abu Dhabi, Abu Dhabi, UAE.
| | - Mainak Dutta
- Department of Biotechnology, BITS Pilani, Dubai Campus, Academic City, Dubai, UAE.
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Hijazi MA, Gessner A, El-Najjar N. Repurposing of Chronically Used Drugs in Cancer Therapy: A Chance to Grasp. Cancers (Basel) 2023; 15:3199. [PMID: 37370809 DOI: 10.3390/cancers15123199] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/06/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Despite the advancement in drug discovery for cancer therapy, drug repurposing remains an exceptional opportunistic strategy. This approach offers many advantages (faster, safer, and cheaper drugs) typically needed to overcome increased challenges, i.e., side effects, resistance, and costs associated with cancer therapy. However, not all drug classes suit a patient's condition or long-time use. For that, repurposing chronically used medications is more appealing. This review highlights the importance of repurposing anti-diabetic and anti-hypertensive drugs in the global fight against human malignancies. Extensive searches of all available evidence (up to 30 March 2023) on the anti-cancer activities of anti-diabetic and anti-hypertensive agents are obtained from multiple resources (PubMed, Google Scholar, ClinicalTrials.gov, Drug Bank database, ReDo database, and the National Institutes of Health). Interestingly, more than 92 clinical trials are evaluating the anti-cancer activity of 14 anti-diabetic and anti-hypertensive drugs against more than 15 cancer types. Moreover, some of these agents have reached Phase IV evaluations, suggesting promising official release as anti-cancer medications. This comprehensive review provides current updates on different anti-diabetic and anti-hypertensive classes possessing anti-cancer activities with the available evidence about their mechanism(s) and stage of development and evaluation. Hence, it serves researchers and clinicians interested in anti-cancer drug discovery and cancer management.
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Affiliation(s)
- Mohamad Ali Hijazi
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Beirut Arab University, Beirut P.O. Box 11-5020, Lebanon
| | - André Gessner
- Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Nahed El-Najjar
- Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, 93053 Regensburg, Germany
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6
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Chang YL, Chou CH, Li YF, Huang LC, Kao Y, Hueng DY, Tsai CK. Antiproliferative and apoptotic effects of telmisartan in human glioma cells. Cancer Cell Int 2023; 23:111. [PMID: 37291545 DOI: 10.1186/s12935-023-02963-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/05/2023] [Indexed: 06/10/2023] Open
Abstract
Glioblastoma is the most common primary central nervous system tumor in adults. Angiotensin II receptor blockers (ARBs) are broadly applied to treat hypertension. Moreover, research has revealed that ARBs have the capacity to suppress the growth of several cancer types. In this study, we assessed the effects of three ARBs with the ability to cross the blood brain barrier (telmisartan, valsartan and fimasartan) on cell proliferation in three glioblastoma multiforme (GBM) cell lines. Telmisartan markedly suppressed the proliferation, migration, and invasion of these three GBM cell lines. Microarray data analysis revealed that telmisartan regulates DNA replication, mismatch repair, and the cell cycle pathway in GBM cells. Furthermore, telmisartan induced G0/G1 phase arrest and apoptosis. The bioinformatic analysis and western blotting results provide evidence that SOX9 is a downstream target of telmisartan. Telmisartan also suppressed tumor growth in vivo in an orthotopic transplant mouse model. Therefore, telmisartan is a potential treatment for human GBM.
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Affiliation(s)
- Yung-Lung Chang
- Department of Biochemistry, National Defense Medical Center, Taipei, 11490, Taiwan
| | - Chung-Hsing Chou
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Cheng-Gong Road, Taipei, 11490, Taiwan
| | - Yao-Feng Li
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, 11490, Taiwan
| | - Li-Chun Huang
- Department of Biochemistry, National Defense Medical Center, Taipei, 11490, Taiwan
| | - Ying Kao
- Division of Neurosurgery, Department of Surgery, Taipei City Hospital Zhongxing Branch, Taipei, Taiwan
| | - Dueng-Yuan Hueng
- Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, 11490, Taiwan
| | - Chia-Kuang Tsai
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Cheng-Gong Road, Taipei, 11490, Taiwan.
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Wagner N, Wagner KD. Pharmacological Utility of PPAR Modulation for Angiogenesis in Cardiovascular Disease. Int J Mol Sci 2023; 24:ijms24032345. [PMID: 36768666 PMCID: PMC9916802 DOI: 10.3390/ijms24032345] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/22/2023] [Accepted: 01/23/2023] [Indexed: 01/27/2023] Open
Abstract
Peroxisome proliferator activated receptors, including PPARα, PPARβ/δ, and PPARγ, are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They play important roles in glucose and lipid metabolism and are also supposed to reduce inflammation and atherosclerosis. All PPARs are involved in angiogenesis, a process critically involved in cardiovascular pathology. Synthetic specific agonists exist for all PPARs. PPARα agonists (fibrates) are used to treat dyslipidemia by decreasing triglyceride and increasing high-density lipoprotein (HDL) levels. PPARγ agonists (thiazolidinediones) are used to treat Type 2 diabetes mellitus by improving insulin sensitivity. PPARα/γ (dual) agonists are supposed to treat both pathological conditions at once. In contrast, PPARβ/δ agonists are not in clinical use. Although activators of PPARs were initially considered to have favorable effects on the risk factors for cardiovascular disease, their cardiovascular safety is controversial. Here, we discuss the implications of PPARs in vascular biology regarding cardiac pathology and focus on the outcomes of clinical studies evaluating their benefits in cardiovascular diseases.
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Mansour SM, Ibrahim RYM. Zofenopril antitumor activity in mice bearing Ehrlich solid carcinoma: Modulation of PI3K/AKT signaling pathway. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902022e19922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Guo XM, Yadav MB, Khan M, Hao CW, Lin CY, Huang T, Wu J, Fan BM, Bian ZX. Bradykinin-Potentiating Peptide-Paclitaxel Conjugate Directed at Ectopically Expressed Angiotensin-Converting Enzyme in Triple-Negative Breast Cancer. J Med Chem 2021; 64:17051-17062. [PMID: 34699215 DOI: 10.1021/acs.jmedchem.1c00705] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer with poor prognosis. Here, we present a peptide-drug conjugate (PDC)-bradykinin-potentiating peptide-paclitaxel (BPP-PTX) conjugate-synthesized by conjugating BPP9a with PTX via a succinyl linker. BPP-PTX targets the angiotensin-converting enzyme (ACE) on TNBC cells. ACE was found to be ectopically expressed in two TNBC cell lines but was absent in both the receptor-positive breast cancer cell line and healthy kidney cell line. Overexpression, knockdown, and competitive inhibition experiments demonstrated ACE-mediated cytotoxicity of BPP-PTX. In vivo, ACE-positive tumors were enriched with BPP-PTX, with the PDC being better tolerated than plain PTX. Compared with plain PTX, BPP-PTX exhibited improved tumor-suppressive effects in MDA-MB-468 xenografted female nude mice. Meanwhile, BPP-PTX resulted in less body weight loss and white blood cell reduction toxicity. These results collectively imply the novelty, efficacy, and low-toxicity profile of BPP-PTX as a potential therapeutic for ACE-positive TNBC.
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Affiliation(s)
- Xuan-Ming Guo
- School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon, Hong Kong 999077, P. R. China
| | - Maruti Balaso Yadav
- YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University, Kunming 650500, P. R. China
| | - Mahjabin Khan
- School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon, Hong Kong 999077, P. R. China
| | - Chao-Wei Hao
- YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University, Kunming 650500, P. R. China
| | - Cheng-Yuan Lin
- School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon, Hong Kong 999077, P. R. China.,YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University, Kunming 650500, P. R. China
| | - Tao Huang
- School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon, Hong Kong 999077, P. R. China
| | - Jiang Wu
- Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai Nationalities University, Xining 810007, P. R. China
| | - Bao-Min Fan
- YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University, Kunming 650500, P. R. China
| | - Zhao-Xiang Bian
- School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon, Hong Kong 999077, P. R. China
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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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Xu K, Han H, Luo Y, Ye H, Lin H, Ni L. The Angiotensin-Converting Enzyme Inhibitory State Promotes the Transformation of Non-Small Cell Lung Cancer Blood Supply Pattern Toward Vasculogenic Mimicry Formation. Front Oncol 2021; 11:663671. [PMID: 34221978 PMCID: PMC8242235 DOI: 10.3389/fonc.2021.663671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 05/27/2021] [Indexed: 11/13/2022] Open
Abstract
Tumor microenvironment plays an important role in tumor proliferation, metastasis, and angiogenesis. Local RAS is a key factor to tumor proliferation and metastasis in NSCLC microenvironment, but its role on angiogenesis and VM formation remains unclear. Although overwhelming majority of previous studies suggested that VM is well established in aggressive tumor and facilitates tumor growth and metastasis, we put forward different views from another angle. We proved that status of tumor blood supply patterns, including VM channels and endothelial vessels, can dynamically exchange with each other along with local RAS fluctuations in microenvironment. Quantitatively, ACE2/ACEI promotes VM formation via Nodal/Notch4 activation; while structurally, ACE2/ACEI leads to a strong and solid structure of VM via inhibition of VE-cadherin internalization. These changes induced by ACE2/ACEI relate to relatively low metastasis rate and comforting prognoses of NSCLC patients.
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Affiliation(s)
- Kandi Xu
- Department of Respiration and Critical Care Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Institute of Respiratory Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Huize Han
- Respiratory and Critical Care Center, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Yexin Luo
- First Clinical Medical College, Anhui Medical University, Anhui, China
| | - Hong Ye
- School of Foreign Studies, Anhui University, Anhui, China
| | - Hongxia Lin
- Department of Respiration and Critical Care Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Institute of Respiratory Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lei Ni
- Department of Respiration and Critical Care Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Institute of Respiratory Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Batais M, Almigbal T, Alotaibi K, Alodhayani A, Alkhushail A, Altheaby A, Alhantoushi M, Alsaad S, Dalbhi SA, Alghamdi Y. Angiotensin converting enzyme inhibitors and risk of lung cancer: A systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e25714. [PMID: 33907158 PMCID: PMC8084080 DOI: 10.1097/md.0000000000025714] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/07/2021] [Accepted: 04/09/2021] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND We performed a meta-analysis to determine whether a consistent relationship exists between the use of angiotensin converting enzyme inhibitors (ACEIs) and the risk of lung cancer. Accordingly, we summarized and reviewed previously published quantitative studies. METHODS Eligible studies with reference lists published before June 1st, 2019 were obtained from searching several databases. Random effects' models were used to summarize the overall estimate of the multivariate adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS Thirteen observational studies involving 458,686 ACEI users were included in the analysis, Overall, pooled risk ratios indicate that ACEIs use was not a risk factor for lung cancer (RR 0.982, 95% C.I. 0.873 - 1.104; P = .76). There was significant heterogeneity between the studies (Q = 52.54; P < .001; I2 = 86.07). There was no significant association between ACEIs use and lung cancer in studies with over five years of ACEIs exposure (RR 0.95, 95% C.I. 0.75 - 1.20; P = .70); and ≤ 5years of exposure to ACEIs (RR 0.98, 95% C.I. 0.83 - 1.15; P = .77). There were no statistically significant differences in the pooled risk ratio obtained according to the study design (Q = 0.65; P = .723) and the comparator regimen (Q = 3.37; P = .19). CONCLUSIONS The use of ACEIs was not associated with an increased risk of lung cancer. Nevertheless, well-designed observational studies with different ethnic populations are still needed to evaluate the long-term (over 10 years) association between ACEIs use and lung cancer.
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Affiliation(s)
- Mohammed Batais
- King Saud University Medical City, College of Medicine, King Saud University
| | - Turky Almigbal
- King Saud University Medical City, College of Medicine, King Saud University
| | | | | | | | | | | | - Saad Alsaad
- King Saud University Medical City, College of Medicine, King Saud University
| | | | - Yasser Alghamdi
- Prince Mohammed Bin Abdulaziz Hospital, Riyadh, Saudi Arabia
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13
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Lin YT, Wang HC, Tsai MH, Su YY, Yang MY, Chien CY. Angiotensin II receptor blockers valsartan and losartan improve survival rate clinically and suppress tumor growth via apoptosis related to PI3K/AKT signaling in nasopharyngeal carcinoma. Cancer 2021; 127:1606-1619. [PMID: 33405241 DOI: 10.1002/cncr.33391] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/29/2020] [Accepted: 10/18/2020] [Indexed: 11/12/2022]
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC) is a common type of head and neck cancer in Asia. Adverse effects occur in over 90% of NPC patients treated with radiotherapy or chemoradiation. Angiotensin II receptor blockers (ARBs) are commonly used to treat hypertension without serious adverse effects. However, the anticancer activity of ARBs in NPC remains unclear. METHODS We investigated the survival impacts of ARBs among NPC patients in a retrospective study. The anticancer effects and related signaling pathways of the ARBs valsartan and losartan were also evaluated in vitro and in vivo. RESULT A total of 927 patients with NPC who had hypertension were enrolled in the study, 272 (29.3%) of whom received ARBs. Kaplan-Meier analysis revealed that patients who used ARBs had higher rates of 5-year overall survival (OS; 87.8% vs 75.1%; P = .002) and disease-specific survival (DSS; 95.4% vs 77.7%; P < .001) than those who did not receive this treatment. Additionally, ARBs inhibited cell proliferation and induced apoptosis by increasing levels of cleaved caspase-3, cleaved caspase-9, and cytochrome C; the cell population in the sub-G1 phase; and caspase-3 activity in NPC-TW01 cells. ARBs inhibited tumor growth and angiogenesis via apoptosis in an NPC xenografts model. Interestingly, ARBs inhibited phosphorylation of PI3K/AKT signaling in vitro and in vivo, which is markedly attributed to their antitumor effects in NPC. CONCLUSION These data indicate that ARBs not only improve 5-year OS and DSS among patients with NPC but also exert antiproliferative and antiangiogenesis effects by inducing apoptosis in NPC, supporting that ARBs may be promising agents for treatment of NPC.
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Affiliation(s)
- Yu-Tsai Lin
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,College of Pharmacy and Health Care, Tajen University, Pingtung, Taiwan
| | - Hung-Chen Wang
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ming-Hsien Tsai
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,College of Pharmacy and Health Care, Tajen University, Pingtung, Taiwan
| | - Yan-Ye Su
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ming-Yu Yang
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Chih-Yen Chien
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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14
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Al-Eitan LN, Alahmad SZ. Pharmacogenomics of genetic polymorphism within the genes responsible for SARS-CoV-2 susceptibility and the drug-metabolising genes used in treatment. Rev Med Virol 2020; 31:e2194. [PMID: 33205496 PMCID: PMC7744885 DOI: 10.1002/rmv.2194] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 12/13/2022]
Abstract
The ongoing outbreak of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) represents a significant challenge to international health. Pharmacogenomics aims to identify the different genetic variations that exist between individuals and populations in order to determine appropriate treatment protocols to enhance the efficacy of drugs and reduce their side‐effects. This literature review provides an overview of recent studies of genetic polymorphisms in genes that mediate the SARS‐CoV‐2 infection mechanism (ACE1, ACE2, TMPRSS2 and CD26). In addition, genetic variations in the drug‐metabolising enzyme genes of several selected drugs used in the treatment of COVID‐19 are summarised. This may help construct an effective health protocol based on genetic biomarkers to optimise response to treatment. Potentially, pharmacogenomics could contribute to the development of effective high‐throughput assays to improve patient evaluation, but their use will also create ethical, medical, regulatory, and legal issues, which should now be considered in the era of personalised medicine.
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Affiliation(s)
- Laith N Al-Eitan
- Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid, Jordan
| | - Saif Z Alahmad
- Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid, Jordan
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15
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Cancer Stem Cells in Head and Neck Metastatic Malignant Melanoma Express Components of the Renin-Angiotensin System. Life (Basel) 2020; 10:life10110268. [PMID: 33147716 PMCID: PMC7694034 DOI: 10.3390/life10110268] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 10/26/2020] [Accepted: 10/30/2020] [Indexed: 12/18/2022] Open
Abstract
Components of the renin-angiotensin system (RAS) are expressed by cancer stem cells (CSCs) in many cancer types. We here investigated expression of the RAS by the CSC subpopulations in human head and neck metastatic malignant melanoma (HNmMM) tissue samples and HNmMM-derived primary cell lines. Immunohistochemical staining demonstrated expression of pro-renin receptor (PRR), angiotensin-converting enzyme (ACE), and angiotensin II receptor 2 (AT2R) in all; renin in one; and ACE2 in none of the 20 HNmMM tissue samples. PRR was localized to cells within the tumor nests (TNs), while AT2R was expressed by cells within the TNs and the peritumoral stroma (PTS). ACE was localized to the endothelium of the tumor microvessels within the PTS. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) detected transcripts for PRR, ACE, ACE2, and AT1R, in all the five HNmMM tissue samples and four HNmMM-derived primary cell lines; renin in one tissue sample and one cell line, and AT2R in none of the five HNmMM tissue samples and cell lines. Western blotting showed variable expression of ACE, PRR, and AT2R, but not ACE2, in six HNmMM tissue samples and two HNmMM-derived primary cell lines. Immunofluorescence staining of two HNmMM tissue samples demonstrated expression of PRR and AT2R by the SOX2+ CSCs within the TNs and the OCT4+ CSCs within the PTS, with ACE localized to the endothelium of the tumor microvessels within the PTS.
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16
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Noble K, Rohaj A, Abegglen LM, Schiffman JD. Cancer therapeutics inspired by defense mechanisms in the animal kingdom. Evol Appl 2020. [DOI: 10.1111/eva.12963] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Affiliation(s)
- Kathleen Noble
- Huntsman Cancer Institute University of Utah Salt Lake City Utah
| | - Aarushi Rohaj
- Huntsman Cancer Institute University of Utah Salt Lake City Utah
| | - Lisa M. Abegglen
- Huntsman Cancer Institute University of Utah Salt Lake City Utah
- Department of Pediatrics University of Utah Salt Lake City Utah
| | - Joshua D. Schiffman
- Huntsman Cancer Institute University of Utah Salt Lake City Utah
- Department of Pediatrics University of Utah Salt Lake City Utah
- PEEL Therapeutics, Inc. Salt Lake City Utah
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17
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Renin-Angiotensin System in Lung Tumor and Microenvironment Interactions. Cancers (Basel) 2020; 12:cancers12061457. [PMID: 32503281 PMCID: PMC7352181 DOI: 10.3390/cancers12061457] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/24/2020] [Accepted: 06/01/2020] [Indexed: 02/08/2023] Open
Abstract
The mechanistic involvement of the renin-angiotensin system (RAS) reaches beyond cardiovascular physiopathology. Recent knowledge pinpoints a pleiotropic role for this system, particularly in the lung, and mainly through locally regulated alternative molecules and secondary pathways. Angiotensin peptides play a role in cell proliferation, immunoinflammatory response, hypoxia and angiogenesis, which are critical biological processes in lung cancer. This manuscript reviews the literature supporting a role for the renin-angiotensin system in the lung tumor microenvironment and discusses whether blockade of this pathway in clinical settings may serve as an adjuvant therapy in lung cancer.
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18
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Kirtonia A, Gala K, Fernandes SG, Pandya G, Pandey AK, Sethi G, Khattar E, Garg M. Repurposing of drugs: An attractive pharmacological strategy for cancer therapeutics. Semin Cancer Biol 2020; 68:258-278. [PMID: 32380233 DOI: 10.1016/j.semcancer.2020.04.006] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/20/2020] [Accepted: 04/22/2020] [Indexed: 02/07/2023]
Abstract
Human malignancies are one of the major health-related issues though out the world and anticipated to rise in the future. The development of novel drugs/agents requires a huge amount of cost and time that represents a major challenge for drug discovery. In the last three decades, the number of FDA approved drugs has dropped down and this led to increasing interest in drug reposition or repurposing. The present review focuses on recent concepts and therapeutic opportunities for the utilization of antidiabetics, antibiotics, antifungal, anti-inflammatory, antipsychotic, PDE inhibitors and estrogen receptor antagonist, Antabuse, antiparasitic and cardiovascular agents/drugs as an alternative approach against human malignancies. The repurposing of approved non-cancerous drugs is an effective strategy to develop new therapeutic options for the treatment of cancer patients at an affordable cost in clinics. In the current scenario, most of the countries throughout the globe are unable to meet the medical needs of cancer patients because of the high cost of the available cancerous drugs. Some of these drugs displayed potential anti-cancer activity in preclinic and clinical studies by regulating several key molecular mechanisms and oncogenic pathways in human malignancies. The emerging pieces of evidence indicate that repurposing of drugs is crucial to the faster and cheaper discovery of anti-cancerous drugs.
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Affiliation(s)
- Anuradha Kirtonia
- Amity Institute of Molecular Medicine and Stem cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida, 201313, India; Equal contribution
| | - Kavita Gala
- Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be University), Vile Parle West, Mumbai, 400056, India; Equal contribution
| | - Stina George Fernandes
- Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be University), Vile Parle West, Mumbai, 400056, India; Equal contribution
| | - Gouri Pandya
- Amity Institute of Molecular Medicine and Stem cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida, 201313, India; Equal contribution
| | - Amit Kumar Pandey
- Amity Institute of Biotechnology, Amity University Haryana, Manesar, Haryana, 122413, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Ekta Khattar
- Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be University), Vile Parle West, Mumbai, 400056, India.
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida, 201313, India.
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19
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Tian Z, Wang Z, Chen Y, Qu S, Liu C, Chen F, Ma L, Zhu J. Bioinformatics Analysis of Prognostic Tumor Microenvironment-Related Genes in the Tumor Microenvironment of Hepatocellular Carcinoma. Med Sci Monit 2020; 26:e922159. [PMID: 32231177 PMCID: PMC7146066 DOI: 10.12659/msm.922159] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Background Growing evidence shows that the tumor microenvironment plays a crucial role in the pathogenesis of hepatocellular carcinoma (HCC). The present work aimed to screen tumor microenvironment-related genes strongly related to prognosis and to construct a prognostic gene expression model for HCC. Material/Methods We downloaded gene expression data of 371 HCC patients in The Cancer Genome Atlas (TCGA). A novel ESTIMATE algorithm was applied to calculate immune scores and stromal scores for each patient. Then, the differentially-expressed genes (DEGs) were detected according to the immune and stromal scores, and tumor microenvironment-related genes were further explored. Univariate, Lasso, and multivariate Cox analyses were performed to build the tumor microenvironment-related prediction model. Results Stromal and immune scores were calculated and were found to be correlated with the 3-year prognosis of HCC patients. DEGs were detected according to the stromal and immune scores. There were 49 genes with prognostic value in both TCGA and ICGC (International Cancer Genome Consortium) considered as prognostic tumor microenvironment-related genes. Univariate, Lasso, and multivariate Cox analyses were conducted. A novel 2-gene signature (IL18RAP and GPR182) was built for HCC 3-year prognosis prediction. The 2-gene signature was regarded as an independent prognostic predictor that was correlated with 3-year survival rate, as shown by Cox regression analysis. Conclusions This study offers a novel 2-gene signature to predict overall survival of patients with HCC, which has the potential to be used as an independent prognostic predictor. Overall, this study reveals more details about the tumor microenvironment in HCC and offers novel candidate biomarkers.
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Affiliation(s)
- Zongbiao Tian
- Department of Gastroenterology, TengZhou Central People's Hospital, Tengzhou, Shandong, China (mainland)
| | - Zheng Wang
- Department of Infectious Diseases, Qilu Hospital, Shandong University, Jinan, Shandong, China (mainland)
| | - Yanfeng Chen
- Department of Gastroenterology, TengZhou Central People's Hospital, Tengzhou, Shandong, China (mainland)
| | - Shuoying Qu
- Department of Clinical Laboratory, Qilu Hospital, Shandong University, Jinan, Shandong, China (mainland)
| | - Changhong Liu
- Department of Gastroenterology, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, China (mainland)
| | - Fengzhe Chen
- Department of Infectious Diseases, Qilu Hospital, Shandong University, Jinan, Shandong, China (mainland)
| | - Lixian Ma
- Department of Infectious Diseases, Qilu Hospital, Shandong University, Jinan, Shandong, China (mainland)
| | - Jie Zhu
- Department of Infectious Diseases, Qilu Hospital, Shandong University, Jinan, Shandong, China (mainland)
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20
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Asgharzadeh F, Hassanian SM, Ferns GA, Khazaei M, Hasanzadeh M. The Therapeutic Potential of Angiotensin-converting Enzyme and Angiotensin Receptor Inhibitors in the Treatment of Colorectal Cancer: Rational Strategies and Recent Progress. Curr Pharm Des 2019; 24:4652-4658. [PMID: 30636592 DOI: 10.2174/1381612825666190111145140] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 01/02/2019] [Indexed: 01/18/2023]
Abstract
Colorectal cancer (CRC) is one of the most common causes of cancer-related death in the world. There is a document that angiotensin (AT) which is found to be involved in the progression of CRC. Furthermore, Angiotensin receptor inhibitors (ARIs) and angiotensin-converting enzyme Inhibitors (ACE-Is) demonstrate activity in CRC by their inhibition of both Insulin-like growth factor 1 (IGF-1) and Vascular endothelial growth factor (VEGF), and therefore present a potentially novel therapeutic strategy in colorectal cancer, which have summarized in the current review. Preclinical studies have illustrated the direct effect of major active mediator angiotensin II (ATII) on the promotion of angiogenesis through VEGF and other proliferative mediators. Suppression of the angiotensin II type I receptor (AT1R) via ACE-Is has shown a reduction in the development of solid tumor and metastasis, particularly CRC incidence, polyp formation, and distant metastasis. MicroRNAs (miRs) are a family of small nucleotides without coding that plays an important role after transcribing hundreds to thousands of non-coding and coding gene. Against this background, the application of anti-hypertensive medications such as losartan might have a therapeutic impact, although further preclinical and clinical studies might provide novel insight into the potentially beneficial effect of ACE-Is in the treatment of colorectal cancer patients.
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Affiliation(s)
- Fereshteh Asgharzadeh
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome 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, United Kingdom
| | - Majid Khazaei
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Malihe Hasanzadeh
- Department of Gynecology Oncology, Woman Health Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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21
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Roth IM, Wickremesekera AC, Wickremesekera SK, Davis PF, Tan ST. Therapeutic Targeting of Cancer Stem Cells via Modulation of the Renin-Angiotensin System. Front Oncol 2019; 9:745. [PMID: 31440473 PMCID: PMC6694711 DOI: 10.3389/fonc.2019.00745] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 07/24/2019] [Indexed: 12/11/2022] Open
Abstract
Cancer stem cells (CSCs) are proposed to be the cells that initiate tumorigenesis and maintain tumor development due to their self-renewal and multipotency properties. CSCs have been identified in many cancer types and are thought to be responsible for treatment resistance, metastasis, and recurrence. As such, targeting CSCs specifically should result in durable cancer treatment. One potential option for targeting CSCs is by manipulation of the renin-angiotensin system (RAS) and pathways that converge on the RAS with numerous inexpensive medications currently in common clinical use. In addition to its crucial role in cardiovascular and body fluid homeostasis, the RAS is vital for stem cell maintenance and differentiation and plays a role in tumorigenesis and cancer prevention, suggesting that these roles may converge and result in modulation of CSC function by the RAS. In support of this, components of the RAS have been shown to be expressed in many cancer types and have been more recently localized to the CSCs in some tumors. Given these roles of the RAS in tumor development, clinical trials using RAS inhibitors either singly or in combination with other therapies are underway in different cancer types. This review outlines the roles of the RAS, with respect to CSCs, and suggests that the presence of components of the RAS in CSCs could offer an avenue for therapeutic targeting using RAS modulators. Due to the nature of the RAS and its crosstalk with numerous other signaling pathways, a systems approach using traditional RAS inhibitors in combination with inhibitors of bypass loops of the RAS and other signaling pathways that converge on the RAS may offer a novel therapeutic approach to cancer treatment.
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Affiliation(s)
- Imogen M Roth
- Gillies McIndoe Research Institute, Wellington, New Zealand
| | - Agadha C Wickremesekera
- Gillies McIndoe Research Institute, Wellington, New Zealand.,Department of Neurosurgery, Wellington Regional Hospital, Wellington, New Zealand
| | - Susrutha K Wickremesekera
- Gillies McIndoe Research Institute, Wellington, New Zealand.,Upper Gastrointestinal, Hepatobiliary and Pancreatic Section, Department of General Surgery, Wellington Regional Hospital, Wellington, New Zealand
| | - Paul F Davis
- Gillies McIndoe Research Institute, Wellington, New Zealand
| | - Swee T Tan
- Gillies McIndoe Research Institute, Wellington, New Zealand.,Wellington Regional Plastic, Maxillofacial and Burns Unit, Hutt Hospital, Wellington, New Zealand
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22
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Chen YH, Lu HI, Lo CM, Huang CC, Hsiao CC, Li SH. The clinical impact of angiotensin-(1-7)/mitochondrial assembly receptor axis in esophageal squamous cell carcinoma patients receiving curative esophagectomy. J Formos Med Assoc 2019; 119:310-318. [PMID: 31202501 DOI: 10.1016/j.jfma.2019.05.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 04/02/2019] [Accepted: 05/28/2019] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Mitochondrial assembly receptor (MasR), a receptor of angiotensin-(1-7), plays an important role in the anti-cancer effect of the peptide hormone. The aim of the current study was to evaluate the crucial role of angiotensin-(1-7)/MasR axis in esophageal squamous cell carcinoma (ESCC) patients who received curative esophagectomy. METHODS The immunohistochemistry of MasR in 90 ESCC patients, including 52 patients with MasR overexpression and 38 patients with low MasR expression, was examined and correlated with their treatment outcomes. Two ESCC cell lines, TE11 and KYSE270, were treated with angiotensin-(1-7) to explore the biological function of MasR. RESULTS A higher percentage of patients in the low MasR expression group experienced tumor recurrence than those in the MasR overexpression group (76% versus 54%, P = 0.029). Patients below 60 years of age and having early T status and negative pathologic N status were found to have significantly better disease-free survival (DFS) and overall survival (OS). Additionally, patients with MasR overexpression had higher DFS (88.1 months versus 50.0 months, p = 0.023) and OS (129.4 months versus 67.5 months, p = 0.028) relative to those with low MasR expression, although there was no significant difference in multivariable analysis. In vitro, these cell lines were treated with angiotensin-(1-7) and the results demonstrated that angiotensin-(1-7) could inhibit the growth of ESCC tumor cells in a dose-dependent manner. CONCLUSION Low expression of MasR may be associated with poor prognosis in ESCC patients receiving curative esophagectomy. Further cohort study with larger population, or a prospective study is warranted to validate this finding.
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Affiliation(s)
- Yen-Hao Chen
- Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Hung-I Lu
- Department of Thoracic & Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Ming Lo
- Department of Thoracic & Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Cheng Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Biobank and Tissue Bank, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chang-Chun Hsiao
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Shau-Hsuan Li
- Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
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23
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Wang Y, Xu H, Fu W, Lu Z, Guo M, Wu X, Sun M, Liu Y, Yu X, Sui D. 20( S)-Protopanaxadiol Inhibits Angiotensin II-Induced Epithelial- Mesenchymal Transition by Downregulating SIRT1. Front Pharmacol 2019; 10:475. [PMID: 31133857 PMCID: PMC6514190 DOI: 10.3389/fphar.2019.00475] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 04/16/2019] [Indexed: 12/11/2022] Open
Abstract
20(S)-Protopanaxadiol (PPD) is one of the major active metabolites in ginseng saponin. Our previous studies revealed a broad spectrum of antitumor effects of PPD. Angiotensin II (Ang II), the biologically active peptide of the renin-angiotensin system (RAS), plays a critical role in the metastasis of various cancers. However, its role in the anti-metastatic effects of PPD is not clearly understood. In this study, we investigated the inhibitory effect of PPD on Ang II-induced epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC) cells, and the potential molecular mechanisms of suppression of NSCLC migration and metastasis by PPD. Treatment of A549 cells with Ang II increased metastases in an experimental model of cancer metastasis in vivo. PPD effectively prevented Ang II-induced EMT, as indicated by upregulation of E-cadherin and downregulation of vimentin. Additionally, Ang II upregulated the class III deacetylase sirtuin 1 (SIRT1) expression in EMT progression, while downregulation of SIRT1 was involved in suppression of Ang II-induced EMT by PPD. Moreover, the inhibitory effect of PPD was reversed by SIRT1 upregulation, and PPD demonstrated synergy with an SIRT1 inhibitor on Ang II-induced EMT. Taken together, our data reveal the mechanism of the anti-metastatic effects of PPD on Ang II-induced EMT and indicate that PPD can be used as an effective anti-tumor treatment.
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Affiliation(s)
- Yuchen Wang
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Huali Xu
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Wenwen Fu
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Zeyuan Lu
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Minyu Guo
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Xueji Wu
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Mingyang Sun
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Yanzhe Liu
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Xiaofeng Yu
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Dayun Sui
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, China
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Rahman N, Khan S. Circular Dichroism Spectroscopy: A Facile Approach for Quantitative Analysis of Captopril and Study of Its Degradation. ACS OMEGA 2019; 4:4252-4258. [PMID: 31459632 PMCID: PMC6648687 DOI: 10.1021/acsomega.8b03384] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 02/12/2019] [Indexed: 05/04/2023]
Abstract
Simple and selective zero- and second-order derivative circular dichroism (CD) spectroscopic methods have been designed for the assay of captopril in commercially available dosage forms. A normal CD spectroscopic scan (zero order) exhibits a negative band at 208 nm (method A) in distilled water. The calibration curve shows a linear response over the concentration range of 10-80 μg mL-1. The second-order derivative (D2) CD spectrum shows one positive band at 208 nm (method B) and one negative band at 225 nm (method C). Linear calibration curves were obtained in the concentration range of 10-70 μg mL-1 for both the methods (B and C). The detection limits were found to be 1.26, 1.48, and 2.38 μg mL-1 for methods A, B, and C, respectively. The study under stressed acidic, basic, and oxidative conditions showed the degradation of captopril. The proposed methods were validated as per ICH guidelines. All the proposed methods were compared with the reference method to demonstrate its suitability for quality control of captopril in its dosage forms.
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25
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Shebl RI. Anti-cancer Potential of Captopril and Botulinum Toxin Type-A and Associated p53 Gene Apototic Stimulating Activity. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2019; 18:1967-1977. [PMID: 32184862 PMCID: PMC7059072 DOI: 10.22037/ijpr.2019.1100800] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Mutational inactivation of p53 is a key player in the development of human cancer. Thus, retrieving the tumor suppressor activity of p53 gene is considered a novel strategy in cancer therapy. Current study aimed to investigate the anti-cancer potentials of botulinum toxin type-A (BTX-A) and captopril as a trial to shed light on effective anti-cancer therapy with lower side effects. Cytotoxic effect of captopril and BTX-A was determined using MTT assay against colon (HCT116) and prostate cancer (DU145) cells compared to their effect on normal vero cells. Anti-proliferation assay and anti-metastatic effect were carried out using trypan blue exclusion method and wound scratch migration test, respectively. The ability of test drugs to induce apoptosis in cancer cells was examined using real time PCR. Recorded data revealed that captopril exhibited a statistically significant cytotoxicity (P < 0.05) to cancer cells (IC50 values of 1.5 and 1.2 mg/mL) with much lower toxicity to normal cells. At the same time, IC50 values post BTX-A treatment were 7.2 and 6.4 U/mL for HCT116 and DU145 cells, respectively without any toxicity to vero cells. Both drugs showed inhibitory potentials on cellular proliferation and the ability of cancer cells to migrate in scratched monolayers was obviously inhibited along with increasing their concentrations. P53 expression levels in captopril and BTX-A treated DU145 cells were elevated by 4 and 2.5 folds, respectively, while lower level of apoptosis induction in HCT116 cells was observed. Accordingly, BTX-A and captopril could present potential anti-cancer candidates through triggering cancer cells towards self-destruction.
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Affiliation(s)
- Rania Ibrahim Shebl
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ahram Canadian University (ACU), Cairo, Egypt
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26
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Zarezadeh A, Rajabi HR, Sheydaei O, Khajehsharifi H. Application of a nano-structured molecularly imprinted polymer as an efficient modifier for the design of captopril drug selective sensor: Mechanism study and quantitative determination. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 94:879-885. [DOI: 10.1016/j.msec.2018.10.042] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 10/04/2018] [Accepted: 10/09/2018] [Indexed: 11/28/2022]
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Qi M, Zhou Y, Liu J, Ou X, Li M, Long X, Ye J, Yu G. AngII induces HepG2 cells to activate epithelial-mesenchymal transition. Exp Ther Med 2018; 16:3471-3477. [PMID: 30233697 PMCID: PMC6143850 DOI: 10.3892/etm.2018.6610] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 06/29/2018] [Indexed: 12/14/2022] Open
Abstract
The present study aimed to determine whether HepG2 can induce epithelial-mesenchymal transition (EMT) via angiotensin II (AngII) simulation. The expression levels of EMT markers vimentin and E-cadherin in cancer tissues and adjacent tissues of patients with hepatocellular carcinoma (HCC) were detected by immunohistochemistry. In addition, HepG2 cells were stimulated with AngII, and the gene and protein expression levels of vimentin and E-cadherin were measured by reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively, whereas cell migration and invasion were assessed using Transwell assays. The AngII inhibitor Ang1-7 and the Ang1-7 inhibitor A779 were added to the system to further evaluate AngII-induced EMT. Compared with that in normal tissue, the expression level of vimentin in HCC tissue was increased, whereas that of E-cadherin was decreased. EMT occurred 48 h following AngII stimulation. The transcription level of E-cadherin in HepG2 cells was decreased, whereas that of vimentin was increased. In addition, the migration and invasion abilities of the cells were increased simultaneously. Ang1-7 partly inhibited AngII-induced EMT. When stimulated at an appropriate time, HepG2 cells have the ability to undergo EMT.
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Affiliation(s)
- Minghua Qi
- Department of Infectious Disease, Beijing University Shenzhen Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Yuanping Zhou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Jikui Liu
- Department of Infectious Disease, Beijing University Shenzhen Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Xi Ou
- Department of Infectious Disease, Beijing University Shenzhen Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Minghua Li
- Department of Infectious Disease, Beijing University Shenzhen Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Xia Long
- Department of Infectious Disease, Beijing University Shenzhen Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Jing Ye
- Department of Infectious Disease, Beijing University Shenzhen Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Guangyin Yu
- Department of Infectious Disease, Beijing University Shenzhen Hospital, Shenzhen, Guangdong 518035, P.R. China
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Ahmadian E, Khosroushahi AY, Eftekhari A, Farajnia S, Babaei H, Eghbal MA. Novel angiotensin receptor blocker, azilsartan induces oxidative stress and NFkB-mediated apoptosis in hepatocellular carcinoma cell line HepG2. Biomed Pharmacother 2018; 99:939-946. [PMID: 29710494 DOI: 10.1016/j.biopha.2018.01.117] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 01/13/2018] [Accepted: 01/24/2018] [Indexed: 12/21/2022] Open
Abstract
Overexpression of renin angiotensin system (RAS) components and nuclear factor-kappa B (NF-kB) has a key role in various cancers. Blockade of RAS and NF-kB pathway has been suggested to reduce cancer cell proliferation. This study aimed to investigate the role of angiotensin II and NF-kB pathway in liver hepatocellular carcinoma cell line (HepG2) proliferation by using azilsartan (as a novel Ag II antagonist) and Bay 11-7082 (as NF-kB inhibitor). HepG2 cells were treated with different concentrations of azilsartan and Bay 11-7082. Cytotoxicity was determined after 24, 48, and 72?h by MTT assay. Reactive oxygen spices (ROS) generation and cytochrome c release were measured following azilsartan and Bay11- 7082 treatment. Apoptosis was analyzed qualitatively by DAPI staining and quantitatively through flow cytometry methodologies and Bax and Bcl-2 mRNA and protein levels were assessed by real time PCR and ELISA methods, respectively. The cytotoxic effects of different concentration of azilsartan and Bay11- 7082 on HepG2 cells were observed as a reduction in cell viability, increased ROS formation, cytochrome c release and apoptosis induction. These effects were found to correlate with a shift in Bax level and a downward trend in the expression of Bcl-2. These findings suggest that azilsartan and Bay11- 7082 in combination or alone have strong potential as an agent for prevention or treatment of liver cancer after further studies.
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Affiliation(s)
- Elham Ahmadian
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Pharmacology and Toxicology Department, Maragheh University of Medical Sciences, Maragheh, Iran; Students' Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Basic Sciences, Maragheh University of Medical Sciences, Maragheh, Iran.
| | - Ahmad Yari Khosroushahi
- Department of Pharmacognosy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Aziz Eftekhari
- Pharmacology and Toxicology Department, Maragheh University of Medical Sciences, Maragheh, Iran; Department of Basic Sciences, Maragheh University of Medical Sciences, Maragheh, Iran; Toxicology Research Center, Maragheh University of Medical Sciences, Maragheh, Iran.
| | - Safar Farajnia
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Hossein Babaei
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaclogy and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammad Ali Eghbal
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaclogy and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran; Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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29
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The effect of angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) on cancer recurrence and survival: a meta-analysis. Eur J Cancer Prev 2018; 26:78-85. [PMID: 27158979 DOI: 10.1097/cej.0000000000000269] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
To assess the current evidence on the potential benefit of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) on cancer recurrence and survival, we comprehensively searched PubMed, Embase, and the Cochrane Library from their inception to April 2013. Two authors screened out duplicates and independently reviewed the eligibility of each study. We included comparative studies comparing the use and nonuse of ACEIs or ARBs in cancer patients. Primary outcomes were disease-free survival (DFS) and overall survival. We included 11 studies with 4964 participants in the final analysis. The meta-analysis showed that the use of ACEIs or ARBs resulted in a significant improvement in DFS [hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.41-0.87; P=0.007)] and overall survival (HR 0.75; 95% CI 0.57-0.99; P=0.04). Even when cancer stage was classified into low (I/II) or high (III/IV), DFS improvement was applied to both low stage (HR 0.56; 95% CI 0.32-0.96; P=0.04) and high stage (HR 0.59; 95% CI 0.37-0.94; P=0.03). Analysis according to cancer type showed benefits in urinary tract cancer (HR 0.22), colorectal cancer (HR 0.22), pancreatic cancer (HR 0.58), and prostate cancer (HR 0.14), but not in breast cancer and hepatocellular cancer. This meta-analysis provides evidence that the use of ACEIs or ARBs in cancer patients can lead to a 40 and 25% reduction in the risk of cancer recurrence and mortality.
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Busby J, McMenamin Ú, Spence A, Johnston BT, Hughes C, Cardwell CR. Angiotensin receptor blocker use and gastro-oesophageal cancer survival: a population-based cohort study. Aliment Pharmacol Ther 2018; 47:279-288. [PMID: 29105106 DOI: 10.1111/apt.14388] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 07/04/2017] [Accepted: 09/26/2017] [Indexed: 12/31/2022]
Abstract
BACKGROUND Angiotensin receptor blockers (ARBs; including candesartan, losartan, olmesartan and valsartan) are widely used to treat hypertension, heart failure and diabetic neuropathy. There is considerable pre-clinical evidence that ARBs can reduce cancer progression, particularly for gastric cancer. Despite this, epidemiological studies have yet to assess the impact of ARB use on gastro-oesophageal cancer survival. AIM To investigate the association between post-diagnosis ARB use and gastro-oesophageal cancer survival. METHODS We selected a cohort of patients with newly-diagnosed gastro-oesophageal cancer between 1998 and 2012 from English cancer registries. We linked to prescription and clinical records from the Clinical Practice Research Datalink, and to death records from the Office for National Statistics. We used time-dependant Cox-regression models to calculate hazard ratios (HRs) comparing gastro-oesophageal cancer-specific mortality between post-diagnosis ARB users and non-users, after adjusting for demographics, comorbidities and post-diagnosis aspirin or statin use. RESULTS Our cohort included 5124 gastro-oesophageal cancer patients, of which 360 used ARBs, and 3345 died due to their gastro-oesophageal cancer during follow-up. After adjustment, ARB users had moderately lower risk of gastro-oesophageal cancer mortality than the non-users (HR = 0.83, 95% CI 0.71-0.98). There was evidence of a dose-response relationship with the lowest HRs observed among patients receiving at least 2 years of prescriptions (HR = 0.42, 95% CI 0.25-0.72). CONCLUSIONS In this large population-based gastro-oesophageal cancer cohort, we found moderately reduced cancer-specific mortality among ARB users. However, confirmation in further independent epidemiological studies with sufficient staging information is required.
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Affiliation(s)
- J Busby
- Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - Ú McMenamin
- Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - A Spence
- Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - B T Johnston
- Belfast Health and Social Care Trust, Belfast, UK
| | - C Hughes
- School of Pharmacy, Clinical and Practice Research Group, Queen's University Belfast, Belfast, UK
| | - C R Cardwell
- Centre for Public Health, Queen's University Belfast, Belfast, UK
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31
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Dolfen J, Boydas EB, Van Speybroeck V, Catak S, Van Hecke K, D’hooghe M. Asymmetric Synthesis of 3,4-Disubstituted 2-(Trifluoromethyl)pyrrolidines through Rearrangement of Chiral 2-(2,2,2-Trifluoro-1-hydroxyethyl)azetidines. J Org Chem 2017; 82:10092-10109. [DOI: 10.1021/acs.joc.7b01241] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Jeroen Dolfen
- SynBioC
Research Group, Department of Sustainable Organic Chemistry and Technology,
Faculty of Bioscience Engineering, Ghent University, Coupure Links
653, B-9000 Ghent, Belgium
| | - Esma Birsen Boydas
- Bogazici University, Department of Chemistry, Bebek, Istanbul 34342, Turkey
| | - Veronique Van Speybroeck
- Center
for Molecular Modeling, Ghent University, Tech Lane Ghent Science Park Campus A, Technologiepark 903, B-9052 Zwijnaarde, Belgium
| | - Saron Catak
- Bogazici University, Department of Chemistry, Bebek, Istanbul 34342, Turkey
- Center
for Molecular Modeling, Ghent University, Tech Lane Ghent Science Park Campus A, Technologiepark 903, B-9052 Zwijnaarde, Belgium
| | - Kristof Van Hecke
- XStruct,
Department of Inorganic and Physical Chemistry, Ghent University, Krijgslaan
281-S3, B-9000 Ghent, Belgium
| | - Matthias D’hooghe
- SynBioC
Research Group, Department of Sustainable Organic Chemistry and Technology,
Faculty of Bioscience Engineering, Ghent University, Coupure Links
653, B-9000 Ghent, Belgium
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32
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Masoudkabir F, Sarrafzadegan N, Gotay C, Ignaszewski A, Krahn AD, Davis MK, Franco C, Mani A. Cardiovascular disease and cancer: Evidence for shared disease pathways and pharmacologic prevention. Atherosclerosis 2017; 263:343-351. [PMID: 28624099 PMCID: PMC6207942 DOI: 10.1016/j.atherosclerosis.2017.06.001] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 05/08/2017] [Accepted: 06/01/2017] [Indexed: 12/21/2022]
Abstract
Cardiovascular disease (CVD) and cancer are leading causes of mortality and morbidity worldwide. Strategies to improve their treatment and prevention are global priorities and major focus of World Health Organization's joint prevention programs. Emerging evidence suggests that modifiable risk factors including diet, sedentary lifestyle, obesity and tobacco use are central to the pathogenesis of both diseases and are reflected in common genetic, cellular, and signaling mechanisms. Understanding this important biological overlap is critical and may help identify novel therapeutic and preventative strategies for both disorders. In this review, we will discuss the shared genetic and molecular factors central to CVD and cancer and how the strategies commonly used for the prevention of atherosclerotic vascular disease can be applied to cancer prevention.
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Affiliation(s)
- Farzad Masoudkabir
- Cardiac Primary Prevention Research Center, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nizal Sarrafzadegan
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran; School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.
| | - Carolyn Gotay
- School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada; Cancer Control Research Program, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada
| | - Andrew Ignaszewski
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Andrew D Krahn
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Margot K Davis
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Christopher Franco
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Arya Mani
- Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
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33
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Liu SF, Kuo HC, Lin MC, Ho SC, Tu ML, Chen YM, Chen YC, Fang WF, Wang CC, Liu GH. Inhaled corticosteroids have a protective effect against lung cancer in female patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study. Oncotarget 2017; 8:29711-29721. [PMID: 28412726 PMCID: PMC5444697 DOI: 10.18632/oncotarget.15386] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Accepted: 01/31/2017] [Indexed: 01/01/2023] Open
Abstract
Whether the use of inhaled corticosteroids (ICS) protects patients with chronic obstructive pulmonary disease (COPD) from lung cancer remains undetermined. In this retrospective nationwide population-based cohort study, we extracted data of 13,686 female COPD patients (ICS users, n = 1,290, ICS non-users, n = 12,396) diagnosed between 1997 and 2009 from the Taiwan's National Health Insurance database. These patients were followed-up until 2011, and lung cancer incidence was determined. Cox regression analysis was used to estimate hazard ratios (HRs) for lung cancer incidence. The time to lung cancer diagnosis was significantly different between ICS users and non-users (10.75 vs. 9.68 years, P < 0.001). Per 100,000 person-years, the lung cancer incidence rate was 235.92 for non-users and 158.67 for users [HR = 0.70 (95% confidence interval {CI}: 0.46-1.09)]. After adjusting for patients' age, income, and comorbidities, a cumulative ICS dose > 39.48 mg was significantly associated with a lower risk of lung cancer [ICS users > 39.48 mg, HR = 0.45 (95% CI: 0.21-0.96)]. Age ≥ 60 years, pneumonia, diabetes mellitus, and hypertension decreased lung cancer risk, whereas pulmonary tuberculosis increased the risk. Our results suggest that ICS have a potential role in lung cancer prevention among female COPD patients.
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Affiliation(s)
- Shih-Feng Liu
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung, Taiwan
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ho-Chang Kuo
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Meng-Chih Lin
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung, Taiwan
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Shu-Chen Ho
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Mei-Lien Tu
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Yu-Mu Chen
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung, Taiwan
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yung-Che Chen
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung, Taiwan
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Wen-Feng Fang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung, Taiwan
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chin-Chou Wang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung, Taiwan
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Guan-Heng Liu
- Department of Senior High School, Li-Chih Valuable School, Kaohsiung, Taiwan
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Wzgarda A, Kleszcz R, Prokop M, Regulska K, Regulski M, Paluszczak J, Stanisz BJ. Unknown face of known drugs – what else can we expect from angiotensin converting enzyme inhibitors? Eur J Pharmacol 2017; 797:9-19. [DOI: 10.1016/j.ejphar.2016.12.031] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Revised: 12/14/2016] [Accepted: 12/20/2016] [Indexed: 02/06/2023]
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Cheng F, Zhao J, Fooksa M, Zhao Z. A network-based drug repositioning infrastructure for precision cancer medicine through targeting significantly mutated genes in the human cancer genomes. J Am Med Inform Assoc 2016; 23:681-91. [PMID: 27026610 DOI: 10.1093/jamia/ocw007] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Accepted: 01/13/2016] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE Development of computational approaches and tools to effectively integrate multidomain data is urgently needed for the development of newly targeted cancer therapeutics. METHODS We proposed an integrative network-based infrastructure to identify new druggable targets and anticancer indications for existing drugs through targeting significantly mutated genes (SMGs) discovered in the human cancer genomes. The underlying assumption is that a drug would have a high potential for anticancer indication if its up-/down-regulated genes from the Connectivity Map tended to be SMGs or their neighbors in the human protein interaction network. RESULTS We assembled and curated 693 SMGs in 29 cancer types and found 121 proteins currently targeted by known anticancer or noncancer (repurposed) drugs. We found that the approved or experimental cancer drugs could potentially target these SMGs in 33.3% of the mutated cancer samples, and this number increased to 68.0% by drug repositioning through surveying exome-sequencing data in approximately 5000 normal-tumor pairs from The Cancer Genome Atlas. Furthermore, we identified 284 potential new indications connecting 28 cancer types and 48 existing drugs (adjusted P < .05), with a 66.7% success rate validated by literature data. Several existing drugs (e.g., niclosamide, valproic acid, captopril, and resveratrol) were predicted to have potential indications for multiple cancer types. Finally, we used integrative analysis to showcase a potential mechanism-of-action for resveratrol in breast and lung cancer treatment whereby it targets several SMGs (ARNTL, ASPM, CTTN, EIF4G1, FOXP1, and STIP1). CONCLUSIONS In summary, we demonstrated that our integrative network-based infrastructure is a promising strategy to identify potential druggable targets and uncover new indications for existing drugs to speed up molecularly targeted cancer therapeutics.
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Affiliation(s)
- Feixiong Cheng
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - Junfei Zhao
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - Michaela Fooksa
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37203, USA Chemical and Physical Biology Program, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Zhongming Zhao
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37203, USA Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37212, USA Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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Tumor growth-inhibitory effect of an angiotensin-converting enzyme inhibitor (captopril) in a lung cancer xenograft model analyzed using 18F-FDG-PET/CT. Nucl Med Commun 2016; 37:139-46. [DOI: 10.1097/mnm.0000000000000404] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Aly MRE, Gobouri AA, Abdel Hafez SH, Saad HA. Synthesis, reactions, and biological activity of some triazine derivatives containing sulfa drug moieties. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2015. [DOI: 10.1134/s1068162015040032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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38
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Kast RE, Karpel-Massler G, Halatsch ME. CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide. Oncotarget 2015; 5:8052-82. [PMID: 25211298 PMCID: PMC4226667 DOI: 10.18632/oncotarget.2408] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs--aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.
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Affiliation(s)
| | - Georg Karpel-Massler
- University of Ulm, Department of Neurosurgery, Albert-Einstein-Allee 23, Ulm, Germany
| | - Marc-Eric Halatsch
- University of Ulm, Department of Neurosurgery, Albert-Einstein-Allee 23, Ulm, Germany
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Papanagnou P, Baltopoulos P, Tsironi M. Marketed nonsteroidal anti-inflammatory agents, antihypertensives, and human immunodeficiency virus protease inhibitors: as-yet-unused weapons of the oncologists' arsenal. Ther Clin Risk Manag 2015; 11:807-19. [PMID: 26056460 PMCID: PMC4445694 DOI: 10.2147/tcrm.s82049] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Experimental data indicate that several pharmacological agents that have long been used for the management of various diseases unrelated to cancer exhibit profound in vitro and in vivo anticancer activity. This is of major clinical importance, since it would possibly aid in reassessing the therapeutic use of currently used agents for which clinicians already have experience. Further, this would obviate the time-consuming process required for the development and the approval of novel antineoplastic drugs. Herein, both pre-clinical and clinical data concerning the antineoplastic function of distinct commercially available pharmacological agents that are not currently used in the field of oncology, ie, nonsteroidal anti-inflammatory drugs, antihypertensive agents, and anti-human immunodeficiency virus agents inhibiting viral protease, are reviewed. The aim is to provide integrated information regarding not only the molecular basis of the antitumor function of these agents but also the applicability of the reevaluation of their therapeutic range in the clinical setting.
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Affiliation(s)
- Panagiota Papanagnou
- Department of Nursing, Faculty of Human Movement and Quality of Life Sciences, University of Peloponnese, Sparta, Greece
| | - Panagiotis Baltopoulos
- Department of Sports Medicine and Biology of Physical Activity, Faculty of Physical Education and Sport Science, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Tsironi
- Department of Nursing, Faculty of Human Movement and Quality of Life Sciences, University of Peloponnese, Sparta, Greece
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Bojarska J, Maniukiewicz W, Fruziński A, Sieroń L, Remko M. Captopril and its dimer captopril disulfide: comparative structural and conformational studies. ACTA CRYSTALLOGRAPHICA SECTION C-STRUCTURAL CHEMISTRY 2015; 71:199-203. [PMID: 25734850 DOI: 10.1107/s2053229615002582] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 02/06/2015] [Indexed: 11/10/2022]
Abstract
The crystal structures of captopril {systematic name: (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid}, C(9)H(15)NO(3)S, (1), and its dimer disulfide metabolite, 1,1'-{disulfanediylbis[(2S)-2-methyl-1-oxopropane-3,1-diyl]}bis-L-proline, C(18)H(28)N(2)O(6)S(2), (2), were determined by single-crystal X-ray diffraction analysis. Compound (1) crystallizes in the orthorhombic space group P2(1)2(1)2(1), while compound (2) crystallizes in the monoclinic space group P2(1), both with one molecule per asymmetric unit. The molecular geometries of (1) and (2) are quite similar, but certain differences appear in the conformations of the five-membered proline rings and the side chains containing the sulfhydryl group. The proline ring adopts an envelope conformation in (1), while in (2) it exists in envelope and slightly deformed half-chair conformations. The conformation adopted by the side chain is extended in (1) and folded in (2). A minimum-energy conformational search using Monte Carlo methods in the aqueous phase reveals that the optimized conformations of the title compounds differ from those determined crystallographically, which depend on their immediate environment. Intermolecular O-H...O and relatively weak C-H...O interactions seem to be effective in both structures and, together with S-H...O and C-H...S contacts, they create three-dimensional networks.
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Affiliation(s)
- Joanna Bojarska
- Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland
| | - Waldemar Maniukiewicz
- Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland
| | - Andrzej Fruziński
- Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland
| | - Lesław Sieroń
- Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland
| | - Milan Remko
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University Bratislava, Odbojarov 10, SK-832 32 Bratislava, Slovakia
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Araújo WF, Naves MA, Ravanini JN, Schor N, Teixeira VPC. Renin-angiotensin system (RAS) blockade attenuates growth and metastatic potential of renal cell carcinoma in mice. Urol Oncol 2015; 33:389.e1-7. [PMID: 25595575 DOI: 10.1016/j.urolonc.2014.11.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 11/27/2014] [Accepted: 11/27/2014] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Renal cell carcinoma (RCC) is the most frequent type of cancer among renal neoplasms in adults and responds poorly to radiotherapy and chemotherapy. There is evidence that blockade of the renin-angiotensin system (RAS) might have antineoplastic effects. The aim of this study was to investigate the effects of RAS blockade on RCC in a murine model. METHODS AND MATERIALS Murine renal cancer cells (Renca) were injected (1 × 10(5)) into the subcapsular space of the left kidney of BALB/c mice (8 wk of age). The animals were divided into 4 groups: a control group (no treatment), angiotensin-receptor blockers group (losartan 100mg/kg/d), angiotensin-converting enzyme inhibitor group (captopril 10mg/kg/d), and angiotensin-receptor blockers +angiotensin-converting enzyme inhibitor group (losartan 100mg/kg/d +captopril 10mg/kg/d). The animals received the drugs by gavage for 21 days after inoculation, beginning 2 days before tumor induction, and were then euthanized. After killing the animals, the kidneys and lungs were removed, weighed, and processed for histopathological and immunohistochemical analyses. Angiogenesis and vascular microvessels were assessed with the antibodies anti-vascular endothelial growth factor and anti-CD34. RESULTS Angiotensin II-inoculated animals developed renal tumors. Treated animals presented smaller tumors, regardless of the therapeutic regimen, and far fewer lung metastases in both quantity and dimension compared with the controls. The expression of vascular endothelial growth factor and CD34 were significantly decreased in renal tumors of treated animals compared with the controls. CONCLUSIONS Our findings suggest that blockade of RAS decreases tumor proliferation and metastatic capacity of RCC in this experimental model.
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Affiliation(s)
- Wedson F Araújo
- Department of Pathology, Universidade Federal de São Paulo (UNIFESP-EPM), São Paulo, Brazil.
| | - Marcelo A Naves
- Department of Medicine, Universidade Federal de São Paulo (UNIFESP-EPM), São Paulo, Brazil
| | - Juliana N Ravanini
- Department of Pathology, Universidade de São Paulo (USP), São Paulo, Brazil
| | - Nestor Schor
- Department of Medicine, Universidade Federal de São Paulo (UNIFESP-EPM), São Paulo, Brazil
| | - Vicente P C Teixeira
- Department of Pathology, Universidade Federal de São Paulo (UNIFESP-EPM), São Paulo, Brazil; Department of Medicine, Universidade Federal de São Paulo (UNIFESP-EPM), São Paulo, Brazil
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Kinetics and mechanism of oxidation of captopril by diperiodatocuprate(III) in aqueous alkaline medium. MONATSHEFTE FUR CHEMIE 2014. [DOI: 10.1007/s00706-014-1329-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Link WT, De Felice A. An FDA overview of rodent carcinogenicity studies of angiotensin II AT-1 receptor blockers: pulmonary adenomas and carcinomas. Regul Toxicol Pharmacol 2014; 70:555-63. [PMID: 25223563 DOI: 10.1016/j.yrtph.2014.09.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Revised: 08/18/2014] [Accepted: 09/04/2014] [Indexed: 12/30/2022]
Abstract
Sipahi et al. (2010) performed a meta-analysis of 5 clinical trials (n=68,402) of 3 Angiotensin II (AngII) receptor subtype AT-1 blockers (ARBs) in cardiovascular disease. It revealed excess new lung cancer diagnoses in the cohorts treated with an ARB and background therapy (0.9% vs. 0.7% in non-ARB control; RR: 1.25; CI: 1.05-1.49; p=0.01). The FDA responded with a larger meta-analysis of 31 clinical trials (n=155,816) of ARBs that found no evidence of any excess of site-specific cancer (lung, breast, prostate), solid/skin cancer or cancer death (FDA safety communication, 3 June 2011). The FDA then re-visited the 19 rodent carcinogenicity assays of 9 ARBs, starting with those for Losartan in 1994, for any evidence of dosage-related lung tumorigenicity in this class. Assays were performed in 5 strains of rats and 5 strains of wild-type and transgenic mice per protocols and dosages sanctioned by FDA's executive carcinogenicity assessment committee (eCAC). Duration was lifetime except for 26-week assays of azilsartan and olmesartan in transgenic Tg rasH2 mice, and an assay of olmesartan in p53(+/-) transgenic mice. The dosages provided exposures approximating, and in most cases up to 20-300times greater than, that in patients. Depending on strain, up to 35% of untreated mice spontaneously developed lung tumors. Regression analysis of placebo-corrected mouse lung tumor incidence collapsed across strains, gender, and ARBs vs. multiples of human exposure revealed no excess lung neoplasia. The R(2) of <0.001 reflected the virtually identical number of treated cohorts with more tumors than its control cohort vs. those with less. Regardless of strain, both control and medicated rats were essentially devoid of lung tumors in the lifetime trials. Accordingly, there was neither promotion of background lung tumors in the mouse, nor initiation of de novo lung tumors in the rat. The negative lung findings in the mouse Tg rasH2 strain are also noteworthy given that, historically, the most prevalent spontaneous tumors in 26week trials in that model are lung adenomas and carcinomas. The negative results of the 19, mostly lifetime, assays for cancer viewed en masse add to the results of the meta-analysis of the shorter clinical trials of ARBs that were benign regardless of statistical method used (random vs. fixed effect), comparator arm (with or without ACE-inhibitors) and major co-factors (smoking or cancer history).
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Affiliation(s)
- William T Link
- Division of Cardiovascular and Renal Drug Products, Center for Drug Evaluation and Research, Office of New Drugs, US Food and Drug Administration, Silver Spring, MD, United States.
| | - Albert De Felice
- Division of Cardiovascular and Renal Drug Products, Center for Drug Evaluation and Research, Office of New Drugs, US Food and Drug Administration, Silver Spring, MD, United States
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Wu JW, Boudreau DM, Park Y, Simonds NI, Freedman AN. Commonly used diabetes and cardiovascular medications and cancer recurrence and cancer-specific mortality: a review of the literature. Expert Opin Drug Saf 2014; 13:1071-99. [PMID: 24999107 DOI: 10.1517/14740338.2014.926887] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Cancer most commonly arises in the elderly who are often burdened with comorbidities. Medications used for treating these comorbidities may alter cancer prognosis. Understanding the impact of these medications on cancer is important in order to make effective evidence-based decisions about managing comorbidities while improving cancer outcomes. AREAS COVERED The evidence on diabetes, statins, antihypertensive and anti-inflammatory medications and their association with cancer recurrence and cancer-specific mortality are reviewed. The strengths and limitations of the existing literature, the current state of the field and future directions are discussed. EXPERT OPINION Metformin and aspirin were associated with a reduced risk of cancer recurrence and cancer-specific mortality. The evidence for statins and antihypertensive medications on cancer survival was inconsistent. There were few studies to suggest that any of the medication classes of interest were associated with negative effects on cancer survival. Methodological shortcomings within observational studies, such as confounding, distinguishing between use of medications pre-cancer versus post-cancer diagnosis/treatment, misclassification of exposures/outcomes, informative censoring and competing risks, must be considered. New observational studies addressing these limitations are essential. Some clinical trials are underway to further investigate the beneficial effects of these drugs and completed trials have confirmed results demonstrated in observational studies.
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Affiliation(s)
- Jennifer W Wu
- McGill University, Epidemiology, Biostatistics, and Occupational Health , 1020 Pine Avenue, Montreal, Quebec, H3A 1A2 , Canada
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Blockade of the renin-angiotensin system inhibits growth of colorectal cancer liver metastases in the regenerating liver. Clin Exp Metastasis 2014; 31:395-405. [PMID: 24442969 DOI: 10.1007/s10585-014-9635-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 01/02/2014] [Indexed: 01/19/2023]
Abstract
Partial hepatectomy (PH), the preferred option for selected patients with colorectal cancer liver metastases (CRCLM), is associated with 40-80% tumor recurrence rates. Renin-angiotensin system (RAS) blockade inhibits tumor growth and has been suggested to improve liver regeneration. We documented the effect of RAS blockade on tumor growth and liver regeneration in a murine model. CRCLM induction followed by 70% PH was performed on 78 CBA mice. Liver regeneration (days 2, 6) and CRCLM tumor load were measured by liver (and tumor) weights, percentage of CRCLM burden and tumor nodule count (days 16, 21). mRNA expression of the RAS components was characterised. Statistical analysis was performed using 2-independent sample T test or Mann-Whitney test (SPSS). Captopril did not impair liver regeneration. By day 21, Captopril decreased tumor burden (percentage of CRCLM in the liver) (48.7 ± 4.7% control, 24.4 ± 6.2 Captopril; p = 0.008), tumor volume (1046.2 ± 200.2 mm(3), 388.3 ± 150.4; p = 0.02), tumor nodule count per image field (181.1 ± 28.5, 68 ± 17.6; p = 0.005) and tumor angiogenesis (71.8 ± 6.4 vessels/mm(2), 43.1 ± 7.6; p = 0.015) compared to controls. Captopril enhanced tumor apoptosis (1 ± 0.2%, 2.5 ± 0.7; p = 0.028). Liver regeneration and tumor development increased liver ACE levels. Blockade of the RAS effectively retarded CRCLM tumor growth at the late stage of tumor development within the regenerating liver without impeding liver regeneration following PH, via anti-angiogenesis and pro-tumor apoptosis. Captopril may be of therapeutic benefit in patients undergoing PH for CRCLM.
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Huo S, Dong J, Song C, Xu J, Shen S, Ren Y, Shi T. Characterization of the reaction products, kinetics and mechanism of oxidation of the drug captopril by platinum(iv) complexes. RSC Adv 2014. [DOI: 10.1039/c3ra45020a] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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Synergistic inhibition of angiogenesis by artesunate and captopril in vitro and in vivo. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:454783. [PMID: 24223058 PMCID: PMC3816047 DOI: 10.1155/2013/454783] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 08/15/2013] [Accepted: 08/20/2013] [Indexed: 02/02/2023]
Abstract
Inhibition of angiogenesis represents one major strategy of cancer chemotherapy. In the present investigation, we investigated the synergism of artesunate and captopril to inhibit angiogenesis. Artesunate is an antimalarial derivative of artemisinin from the Chinese medicinal plant, Artemisia annua L., which also reveals profound anticancer activity in vitro and in vivo. Captopril is an angiotensin I-converting (ACE) inhibitor, which is well established in Western academic medicine. Both compounds inhibited migration of human umbilical vein endothelial cells (HUVECs) in vitro. The combination of both drugs resulted in synergistically inhibited migration. Whereas artesunate inhibited HUVEC growth in the XTT assay, captopril did not, indicating independent modes of action. We established a chorioallantoic membrane (CAM) assay of quail embryos (Coturnix coturnix L.) and a computer-based evaluation routine for quantitative studies on vascularization processes in vivo. Artesunate and captopril inhibited blood vessel formation and growth. For the first time, we demonstrated that both drugs revealed synergistic effects when combined. These results may also have clinical impact, since cardiovascular diseases and cancer frequently occur together in older cancer patients. Therefore, comorbid patients may take advantage, if they take captopril to treat cardiovascular symptoms and artesunate to treat cancer.
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Badi SS, Tuwar SM. Kinetics and Mechanism of Oxidation of Captopril by Hexacyanoferrate(III) in Aqueous Acidic Medium. J SOLUTION CHEM 2013. [DOI: 10.1007/s10953-013-0044-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Wen SW, Ager EI, Neo J, Christophi C. The renin angiotensin system regulates Kupffer cells in colorectal liver metastases. Cancer Biol Ther 2013; 14:720-7. [PMID: 23792575 DOI: 10.4161/cbt.25092] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Blockade of the renin angiotensin system (RAS) can inhibit tumor growth and this may be mediated via undefined immunomodulatory actions. This study investigated the effects of RAS blockade on liver macrophages (Kupffer cells; KCs) in an orthotopic murine model of colorectal cancer (CRC) liver metastases. Here we showed that pharmacological targeting of the RAS [ANG II (31.25 µg/kg/h i.p.), ANG-(1-7) (24 µg/kg/h i.p.) or the ACE inhibitor; captopril (750 mg/kg/d i.p.)] altered endogenous KC numbers in the tumor-bearing liver throughout metastatic growth. Captopril, and to a lesser extent ANG-(1-7), increased KC numbers in the liver but not tumor. KCs were found to express the key RAS components: ACE and AT1R. Treatment with captopril and ANG II increased the number of AT1R-expressing KCs, although total KC numbers were not affected by ANG II. Captopril (0.1 µM) also increased macrophage invasion in vitro. Additionally, captopril was administered with KC depletion before tumor induction (day 0) or at established metastatic growth (day 18) using gadolinium chloride (GdCl 3; 20 mg/kg). Livers were collected at day 21 and quantitative stereology used as a measure of tumor burden. Captopril reduced growth of CRC liver metastases. However, when captopril was combined with early KC depletion (day 0) tumor growth was significantly increased compared with captopril alone. In contrast, late KC depletion (day 18) failed to influence the anti-tumor effects of captopril. The result of these studies suggests that manipulation of the RAS can alter KC numbers and may subsequently influence progression of CRC liver metastases.
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Affiliation(s)
- Shu Wen Wen
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
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Kuniyasu H. Multiple roles of angiotensin in colorectal cancer. World J Clin Oncol 2012; 3:150-4. [PMID: 23293754 PMCID: PMC3536833 DOI: 10.5306/wjco.v3.i12.150] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Revised: 09/28/2012] [Accepted: 11/17/2012] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) cells express renin and chymase through which they can activate angiotensin. Renin expression is induced by hyperglycemic conditions. As angiotensinogen is produced in the liver, CRC cells that can activate angiotensin have an enhanced ability to metastasize to this organ. In human CRC cases, patients with diabetes have higher activities of rennin and angiotensin-II in primary tumors, and on average, have a more progressed disease stage, especially with respect to liver metastasis. These patients exhibit a stronger association with Hemoglobin A1c levels and metastasis compared to patients without diabetes. In a combined diabetes/CRC liver metastasis mouse model, concurrent treatment with anti-angiotensin and hypoglycemic agents shows a synergic effect in terms of reduced liver metastasis and improved survival. The effect of anti-angiotensin treatment and blood sugar control as a baseline management for colon cancer patients with diabetes needs to be examined in clinical trials to establish whether it can prevent liver metastasis.
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Affiliation(s)
- Hiroki Kuniyasu
- Hiroki Kuniyasu, Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
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