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Mohammed S, Alvarado V, Jiang YP, Velazquez FN, Alexander ME, Alvarez FA, Lambadis D, Chiappone SB, Ostermeyer-Fay AG, Zhang L, Shamseddine AA, Canals D, Snider AJ, Lin RZ, Hannun YA, Clarke CJ. A Critical Role for Neutral Sphingomyelinase-2 in Doxorubicin-induced Cardiotoxicity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.20.644150. [PMID: 40166217 PMCID: PMC11957120 DOI: 10.1101/2025.03.20.644150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Although Doxorubicin (Dox) is an effective chemotherapeutic, its clinical utility is limited by a cumulative dose-dependent cardiotoxicity. While mechanisms underlying this cardiotoxicity have been investigated, strategies targeting these pathways have had marginal effects or had potential to interfere with Dox's anti-cancer activity. Sphingolipids (SL) are central to the chemotherapy response in multiple cancers, yet comparatively little is known about their role in non-transformed tissue, and actionable SL targets have not been identified. Here, we identified the SL enzyme neutral sphingomyelinase-2 (nSMase2) as a crucial downstream effector of Dox that is critical for chronic Dox-induced cardiotoxicity. In vitro studies showed that Dox treatment induces nSMase2 mRNA, protein, activity, and Cer accumulation in cardiomyocytes (CM) but not in cardiac fibroblasts. Mechanistically, nSMase2 induction was downstream of Top2B and p53, two previously identified molecular regulators of Dox-induced cardiotoxicity. In vivo studies in a chronic Dox model of cardiotoxicity found that loss of nSMase2 activity-null fro/fro mice were significantly protected from Dox-induced cardiac damage, exhibiting maintained ejection fraction, fractional shortening, and reduced left ventricle mass compared to wild-type littermates. Biologically, nSMase2 was dispensable for Dox-induced cell death but was important for Dox-induced CM senescence both in vitro and in vivo . Microarray analysis identified the dual specificity phosphatase DUSP4 as a downstream target of nSMase2 in vitro in Dox-treated CMs and in vivo in the chronic Dox-treated heart. Taken together, these results establish nSMase2 as a key component of the DNA damage response pathway in CMs and define a critical role for nSMase2 as a SL mediator of Dox-induced cardiotoxicity through effects on CM senescence. In addition to cementing a role for SLs in Dox effects in normal tissue, this study further advances nSMase2 as a target of interest for cardioprotection.
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Trimarchi G, Teresi L, Licordari R, Pingitore A, Pizzino F, Grimaldi P, Calabrò D, Liotta P, Micari A, de Gregorio C, Di Bella G. Transient Left Ventricular Dysfunction from Cardiomyopathies to Myocardial Viability: When and Why Cardiac Function Recovers. Biomedicines 2024; 12:1051. [PMID: 38791012 PMCID: PMC11117605 DOI: 10.3390/biomedicines12051051] [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: 04/15/2024] [Revised: 04/30/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
Transient left ventricular dysfunction (TLVD), a temporary condition marked by reversible impairment of ventricular function, remains an underdiagnosed yet significant contributor to morbidity and mortality in clinical practice. Unlike the well-explored atherosclerotic disease of the epicardial coronary arteries, the diverse etiologies of TLVD require greater attention for proper diagnosis and management. The spectrum of disorders associated with TLVD includes stress-induced cardiomyopathy, central nervous system injuries, histaminergic syndromes, various inflammatory diseases, pregnancy-related conditions, and genetically determined syndromes. Furthermore, myocardial infarction with non-obstructive coronary arteries (MINOCA) origins such as coronary artery spasm, coronary thromboembolism, and spontaneous coronary artery dissection (SCAD) may also manifest as TLVD, eventually showing recovery. This review highlights the range of ischemic and non-ischemic clinical situations that lead to TLVD, gathering conditions like Tako-Tsubo Syndrome (TTS), Kounis syndrome (KS), Myocarditis, Peripartum Cardiomyopathy (PPCM), and Tachycardia-induced cardiomyopathy (TIC). Differentiation amongst these causes is crucial, as they involve distinct clinical, instrumental, and genetic predictors that bode different outcomes and recovery potential for left ventricular function. The purpose of this review is to improve everyday clinical approaches to treating these diseases by providing an extensive survey of conditions linked with TLVD and the elements impacting prognosis and outcomes.
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Affiliation(s)
- Giancarlo Trimarchi
- Department of Clinical and Experimental Medicine, Cardiology Unit, University of Messina, 98100 Messina, Italy; (L.T.); (P.G.); (D.C.); (P.L.); (C.d.G.); (G.D.B.)
| | - Lucio Teresi
- Department of Clinical and Experimental Medicine, Cardiology Unit, University of Messina, 98100 Messina, Italy; (L.T.); (P.G.); (D.C.); (P.L.); (C.d.G.); (G.D.B.)
| | - Roberto Licordari
- Department of Biomedical and Dental Sciences and Morphological and Functional Imaging, University of Messina, 98100 Messina, Italy; (R.L.); (A.M.)
| | - Alessandro Pingitore
- Istituto di Fisiologia Clinica, Clinical Physiology Institute, CNR, 56124 Pisa, Italy;
| | - Fausto Pizzino
- Cardiology Unit, Heart Centre, Fondazione Gabriele Monasterio—Regione Toscana, 54100 Massa, Italy;
| | - Patrizia Grimaldi
- Department of Clinical and Experimental Medicine, Cardiology Unit, University of Messina, 98100 Messina, Italy; (L.T.); (P.G.); (D.C.); (P.L.); (C.d.G.); (G.D.B.)
| | - Danila Calabrò
- Department of Clinical and Experimental Medicine, Cardiology Unit, University of Messina, 98100 Messina, Italy; (L.T.); (P.G.); (D.C.); (P.L.); (C.d.G.); (G.D.B.)
| | - Paolo Liotta
- Department of Clinical and Experimental Medicine, Cardiology Unit, University of Messina, 98100 Messina, Italy; (L.T.); (P.G.); (D.C.); (P.L.); (C.d.G.); (G.D.B.)
| | - Antonio Micari
- Department of Biomedical and Dental Sciences and Morphological and Functional Imaging, University of Messina, 98100 Messina, Italy; (R.L.); (A.M.)
| | - Cesare de Gregorio
- Department of Clinical and Experimental Medicine, Cardiology Unit, University of Messina, 98100 Messina, Italy; (L.T.); (P.G.); (D.C.); (P.L.); (C.d.G.); (G.D.B.)
| | - Gianluca Di Bella
- Department of Clinical and Experimental Medicine, Cardiology Unit, University of Messina, 98100 Messina, Italy; (L.T.); (P.G.); (D.C.); (P.L.); (C.d.G.); (G.D.B.)
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Yan T, Yu H, Li T, Dong Y. Mechanisms of Cardiovascular Toxicities Induced by Cancer Therapies and Promising Biomarkers for Their Prediction: A Scoping Review. Heart Lung Circ 2024; 33:605-638. [PMID: 38242833 DOI: 10.1016/j.hlc.2023.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/16/2023] [Accepted: 12/01/2023] [Indexed: 01/21/2024]
Abstract
AIM With the advancement of anti-cancer medicine, cardiovascular toxicities due to cancer therapies are common in oncology patients, resulting in increased mortality and economic burden. Cardiovascular toxicities caused by cancer therapies include different severities of cardiomyopathy, arrhythmia, myocardial ischaemia, hypertension, and thrombosis, which may lead to left ventricular dysfunction and heart failure. This scoping review aimed to summarise the mechanisms of cardiovascular toxicities following various anti-cancer treatments and potential predictive biomarkers for early detection. METHODS PubMed, Cochrane, Embase, Web of Science, Scopus, and CINAHL databases were searched for original studies written in English related to the mechanisms of cardiovascular toxicity induced by anti-cancer therapies, including chemotherapy, targeted therapy, immunotherapy, radiation therapy, and relevant biomarkers. The search and title/abstract screening were conducted independently by two reviewers, and the final analysed full texts achieved the consensus of the two reviewers. RESULTS A total of 240 studies were identified based on their titles and abstracts. In total, 107 full-text articles were included in the analysis. Cardiomyocyte and endothelial cell apoptosis caused by oxidative stress injury, activation of cell apoptosis, blocking of normal cardiovascular protection signalling pathways, overactivation of immune cells, and myocardial remodelling were the main mechanisms. Promising biomarkers for anti-cancer therapies related to cardiovascular toxicity included placental growth factor, microRNAs, galectin-3, and myeloperoxidase for the early detection of cardiovascular toxicity. CONCLUSION Understanding the mechanisms of cardiovascular toxicity following various anti-cancer treatments could provide implications for future personalised treatment methods to protect cardiovascular function. Furthermore, specific early sensitive and stable biomarkers of cardiovascular system damage need to be identified to predict reversible damage to the cardiovascular system and improve the effects of anti-cancer agents.
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Affiliation(s)
- Tingting Yan
- Nursing Department, Liaocheng Vocational and Technical College, Liaocheng City, Shandong Province, China
| | - Hailong Yu
- Department of Gastrointestinal Surgery, Liaocheng People's Hospital, Liaocheng City, Shandong Province, China
| | - Tai Li
- Nursing Department, Liaocheng Vocational and Technical College, Liaocheng City, Shandong Province, China
| | - Yanhong Dong
- Alice Lee Centre for Nursing Studies, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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Wang T, Shi S, Shi Y, Jiang P, Hu G, Ye Q, Shi Z, Yu K, Wang C, Fan G, Zhao S, Ma H, Chang ACY, Li Z, Bian Q, Lin CP. Chemical-induced phase transition and global conformational reorganization of chromatin. Nat Commun 2023; 14:5556. [PMID: 37689690 PMCID: PMC10492836 DOI: 10.1038/s41467-023-41340-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 08/29/2023] [Indexed: 09/11/2023] Open
Abstract
Chemicals or drugs can accumulate within biomolecular condensates formed through phase separation in cells. Here, we use super-resolution imaging to search for chemicals that induce phase transition within chromatin at the microscale. This microscopic screening approach reveals that adriamycin (doxorubicin) - a widely used anticancer drug that is known to interact with chromatin - specifically induces visible local condensation and global conformational change of chromatin in cancer and primary cells. Hi-C and ATAC-seq experiments systematically and quantitatively demonstrate that adriamycin-induced chromatin condensation is accompanied by weakened chromatin interaction within topologically associated domains, compartment A/B switching, lower chromatin accessibility, and corresponding transcriptomic changes. Mechanistically, adriamycin complexes with histone H1 and induces phase transition of H1, forming fibrous aggregates in vitro. These results reveal a phase separation-driven mechanism for a chemotherapeutic drug.
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Affiliation(s)
- Tengfei Wang
- School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China
| | - Shuxiang Shi
- School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China
- Lingang Laboratory, 200031, Shanghai, China
| | - Yuanyuan Shi
- Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200125, Shanghai, China
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Peipei Jiang
- Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200125, Shanghai, China
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Ganlu Hu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 201210, Shanghai, China
| | - Qinying Ye
- School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China
| | - Zhan Shi
- School of Physical Science and Technology, ShanghaiTech University, 201210, Shanghai, China
| | - Kexin Yu
- School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China
- iHuman Institute, ShanghaiTech University, 201010, Shanghai, China
| | - Chenguang Wang
- Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200125, Shanghai, China
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
- Department of Cardiology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guoping Fan
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 201210, Shanghai, China
| | - Suwen Zhao
- School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China
- iHuman Institute, ShanghaiTech University, 201010, Shanghai, China
| | - Hanhui Ma
- School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China
| | - Alex C Y Chang
- Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200125, Shanghai, China
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
- Department of Cardiology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhi Li
- School of Physical Science and Technology, ShanghaiTech University, 201210, Shanghai, China
| | - Qian Bian
- Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200125, Shanghai, China.
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
| | - Chao-Po Lin
- School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China.
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Kwok C, Nolan M. Cardiotoxicity of anti-cancer drugs: cellular mechanisms and clinical implications. Front Cardiovasc Med 2023; 10:1150569. [PMID: 37745115 PMCID: PMC10516301 DOI: 10.3389/fcvm.2023.1150569] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 07/17/2023] [Indexed: 09/26/2023] Open
Abstract
Cardio-oncology is an emerging field that seeks to enhance quality of life and longevity of cancer survivors. It is pertinent for clinicians to understand the cellular mechanisms of prescribed therapies, as this contributes to robust understanding of complex treatments and off-target effects, improved communication with patients, and guides long term care with the goal to minimise or prevent cardiovascular complications. Our aim is to review the cellular mechanisms of cardiotoxicity involved in commonly used anti-cancer treatments and identify gaps in literature and strategies to mitigate cardiotoxicity effects and guide future research endeavours.
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Affiliation(s)
- Cecilia Kwok
- Department of Medicine, Western Health, Melbourne, VIC, Australia
| | - Mark Nolan
- Department of Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Cardiovascular Imaging, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
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Rahimi K, Amoozgar H, Zareifar S, Shahriari M, Zekavat OR, Karimi M, Fathpour G, Saleh F, Shakibazad N, Bordbar S, Bordbar M. Cardioprotective effects of deferoxamine in acute and subacute cardiotoxicities of doxorubicin: a randomized clinical trial. Egypt Heart J 2023; 75:21. [PMID: 36961611 PMCID: PMC10039151 DOI: 10.1186/s43044-023-00347-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 03/13/2023] [Indexed: 03/25/2023] Open
Abstract
BACKGROUND Cardiotoxicity is a major concern following doxorubicin (DOX) use in the treatment of malignancies. We aimed to investigate whether deferoxamine (DFO) can prevent acute cardiotoxicity in children with cancer who were treated with DOX as part of their chemotherapy. RESULTS Sixty-two newly-diagnosed pediatric cancer patients aged 2-18 years with DOX as part of their treatment regimens were assigned to three groups: group 1 (no intervention, n = 21), group II (Deferoxamine (DFO) 10 times DOX dose, n = 20), and group III (DFO 50 mg/kg, n = 21). Patients in the intervention groups were pretreated with DFO 8-h intravenous infusion in each chemotherapy course during and after completion of DOX infusion. Conventional and tissue Doppler echocardiography, serum concentrations of human brain natriuretic peptide (BNP), and cardiac troponin I (cTnI) were checked after the last course of chemotherapy. Sixty patients were analyzed. The level of cTnI was < 0.01 in all patients. Serum BNP was significantly lower in group 3 compared to control subjects (P = 0.036). No significant differences were observed in the parameters of Doppler echocardiography. Significant lower values of tissue Doppler late diastolic velocity at the lateral annulus of the tricuspid valve were noticed in group 3 in comparison with controls. By using Pearson analysis, tissue Doppler systolic velocity of the septum showed a marginally significant negative correlation with DOX dose (P = 0.05, r = - 0.308). No adverse effect was reported in the intervention groups. CONCLUSIONS High-dose DFO (50 mg/kg) may serve as a promising cardioprotective agent at least at the molecular level in cancer patients treated with DOX. Further multicenter trials with longer follow-ups are needed to investigate its protective role in delayed DOX-induced cardiac damage. Trial registration IRCT, IRCT2016080615666N5. Registered 6 September 2016, http://www.irct.ir/IRCT2016080615666N5 .
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Affiliation(s)
- Kosar Rahimi
- Department of Pediatrics, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamid Amoozgar
- Department of Pediatrics, and Divisions of Pediatric Cardiology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soheila Zareifar
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahdi Shahriari
- Department of Pediatrics, and Divisions of Pediatric Hematology and Oncology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omid Reza Zekavat
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehran Karimi
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Gholamreza Fathpour
- Department of Pediatrics, and Divisions of Pediatric Hematology and Oncology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fazl Saleh
- Department of Pediatrics, and Divisions of Pediatric Hematology and Oncology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nader Shakibazad
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Bushehr University of Medical Sciences, Bushehr, Iran
| | - Shayan Bordbar
- Students Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammadreza Bordbar
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Morelli MB, Bongiovanni C, Da Pra S, Miano C, Sacchi F, Lauriola M, D’Uva G. Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms and Strategies for Cardioprotection. Front Cardiovasc Med 2022; 9:847012. [PMID: 35497981 PMCID: PMC9051244 DOI: 10.3389/fcvm.2022.847012] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 03/03/2022] [Indexed: 12/13/2022] Open
Abstract
Chemotherapy and targeted therapies have significantly improved the prognosis of oncology patients. However, these antineoplastic treatments may also induce adverse cardiovascular effects, which may lead to acute or delayed onset of cardiac dysfunction. These common cardiovascular complications, commonly referred to as cardiotoxicity, not only may require the modification, suspension, or withdrawal of life-saving antineoplastic therapies, with the risk of reducing their efficacy, but can also strongly impact the quality of life and overall survival, regardless of the oncological prognosis. The onset of cardiotoxicity may depend on the class, dose, route, and duration of administration of anticancer drugs, as well as on individual risk factors. Importantly, the cardiotoxic side effects may be reversible, if cardiac function is restored upon discontinuation of the therapy, or irreversible, characterized by injury and loss of cardiac muscle cells. Subclinical myocardial dysfunction induced by anticancer therapies may also subsequently evolve in symptomatic congestive heart failure. Hence, there is an urgent need for cardioprotective therapies to reduce the clinical and subclinical cardiotoxicity onset and progression and to limit the acute or chronic manifestation of cardiac damages. In this review, we summarize the knowledge regarding the cellular and molecular mechanisms contributing to the onset of cardiotoxicity associated with common classes of chemotherapy and targeted therapy drugs. Furthermore, we describe and discuss current and potential strategies to cope with the cardiotoxic side effects as well as cardioprotective preventive approaches that may be useful to flank anticancer therapies.
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Affiliation(s)
| | - Chiara Bongiovanni
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems (INBB), Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Silvia Da Pra
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems (INBB), Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Carmen Miano
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems (INBB), Bologna, Italy
| | - Francesca Sacchi
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems (INBB), Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Mattia Lauriola
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Gabriele D’Uva
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems (INBB), Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
- *Correspondence: Gabriele D’Uva,
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Ramasamy M, Balasubramanian B, Punniyakotti P, Vijaya Anand A, Meyyazhagan A, Velayuthaprabhu S, Rengarajan RL, Issara U, Liu W. Cardio-protective effects of Terminalia catappa leaves and Terminalia chebula fruit extract in doxorubicin-induced cardiomyopathy in rats. Biomarkers 2022; 27:488-495. [PMID: 35400254 DOI: 10.1080/1354750x.2022.2064550] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
INTRODUCTION The cardio-protective effects of Terminalia catappa and Terminalia chebula are well-recognized in Ayurveda for its antimicrobial, antidiabetic and antioxidant potentials. The present study evaluates the effects of T. catappa leaves (Tct.LE) and T. chebula fruits (Tce.FE) against doxorubicin (DOX)-induced rats through analysis of the cardiac biomarkers, tricarboxylic acid (TCA) cycle enzymes and respiratory chain enzymes for their cardio-protective properties. Materials and methods: This study includes 42 adult male Albino Wistar rats randomized into seven groups for 21-days. Groups were categorized as control; DOX (1.5 mg/kg) induced negative control; basal diet with 300 mg/kg of Tct.LE, with 300 mg/kg Tce.FE; DOX with 300 mg/kg of Tct.LE, Tce.FE, and propranolol (25mg/kg). Results and Discussion: The doses of 300 mg/kg of both plants have a significant effect on the TCA cycle, respiratory and lysosomal enzymes activity. The troponin levels are significantly reduced in plant treated group than the DOX-treated rats when compared with the control and propranolol treated group. Likewise, the increased level of creatine kinase-muscle/MB, creatine kinase and lipid profile in the DOX-treated animals were significantly reduced upon being treated with extracts. Conclusion: The cardio-protective activity of Tct.LE leaves and Tce.FE indicate its potential use in the management of cardiovascular diseases. CLINICAL SIGNIFICANCE The prevalence of cardiovascular disease is increasing day-by-day in this industrial world with leading cause of mortality and morbidity. Many researches are presently concentrated on the plant-based medicine due to its safety and free from side effects. Hence, the present study aims to document the potential cardio-protective benefits of Terminalia catappa and Terminalia chebula.
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Affiliation(s)
- Manikandan Ramasamy
- Department of Biochemistry, Shrimati Indira Gandhi College, Trichirappalli-620 002, Tamil Nadu, India
| | | | - Panneerselvam Punniyakotti
- Department of Biochemistry, Kanchi Shri Krishna College of Arts and Science, Kancheepuram-631 551, Tamil Nadu, India
| | - Arumugam Vijaya Anand
- Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore- 641 046, Tamil Nadu, India
| | - Arun Meyyazhagan
- Department of Obstetrics and Gynecology and Centre for Perinatal and Reproductive Medicine, University of Perugia, Perugia, Italy
| | | | | | - Utthapon Issara
- Division of Food Science and Technology Management, Faculty of Science and Technology, Rajamangala University of Technology Thanyaburi, 12110, Thailand
| | - Wenchao Liu
- Department of Animal Science, College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, P. R. China
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Kabir S, Lingappa N, Mayrovitz H. Potential Therapeutic Treatments for Doxorubicin-Induced Cardiomyopathy. Cureus 2022; 14:e21154. [PMID: 35165604 PMCID: PMC8833288 DOI: 10.7759/cureus.21154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 01/12/2022] [Indexed: 11/05/2022] Open
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Primary prevention of chronic anthracycline cardiotoxicity with ACE inhibitor is temporarily effective in rabbits, but benefits wane in post-treatment follow-up. Clin Sci (Lond) 2021; 136:139-161. [PMID: 34878093 DOI: 10.1042/cs20210836] [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: 08/26/2021] [Revised: 11/16/2021] [Accepted: 12/08/2021] [Indexed: 11/17/2022]
Abstract
Angiotensin-converting enzyme inhibitors (ACEis) have been used to treat anthracycline-induced cardiac dysfunction, and they appear beneficial for secondary prevention in high-risk patients. However, it remains unclear whether they truly prevent anthracycline-induced cardiac damage and provide long-lasting cardioprotection. This study aimed to examine the cardioprotective effects of perindopril on chronic anthracycline cardiotoxicity in a rabbit model previously validated with the cardioprotective agent dexrazoxane with focus on post-treatment follow-up (FU). Chronic cardiotoxicity was induced by daunorubicin (3 mg/kg/week for 10 weeks). Perindopril (0.05 mg/kg/day) was administered before and throughout chronic daunorubicin treatment. After the completion of treatment, significant benefits were observed in perindopril co-treated animals, particularly full prevention of daunorubicin-induced mortality and prevention or significant reductions in cardiac dysfunction, plasma cardiac troponin T levels, morphological damage, and most of the myocardial molecular alterations. However, these benefits significantly waned during 3 weeks of drug-free FU, which was not salvageable by administering a higher perindopril dose. In the longer (10-week) FU period, further worsening of left ventricular function and morphological damage occurred together with heart failure-related mortality. Continued perindopril treatment in the FU period did not reverse this trend but prevented heart failure-related mortality and reduced the severity of the progression of cardiac damage. These findings contrasted with the robust long-lasting protection observed previously for dexrazoxane in the same model. Hence, in this study, perindopril provided only temporary control of anthracycline cardiotoxicity development, which may be associated with the lack of effects on anthracycline-induced and topoisomerase II beta-dependent DNA damage responses in the heart.
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11
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Cai H, Men H, Cao P, Zheng Y. Mechanism and prevention strategy of a bidirectional relationship between heart failure and cancer (Review). Exp Ther Med 2021; 22:1463. [PMID: 34737803 PMCID: PMC8561773 DOI: 10.3892/etm.2021.10898] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 09/16/2021] [Indexed: 12/11/2022] Open
Abstract
The relationship between cancer and heart failure has been extensively studied in the last decade. These studies have focused on describing heart injury caused by certain cancer treatments, including radiotherapy, chemotherapy and targeted therapy. Previous studies have demonstrated a higher incidence of cancer in patients with heart failure. Heart failure enhances an over-activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, and subsequently promotes cancer development. Other studies have found that heart failure and cancer both have a common pathological origin, flanked by chronic inflammation in certain organs. The present review aims to summarize and describe the recent discoveries, suggested mechanisms and relationships between heart failure and cancer. The current review provides more ideas on clinical prevention strategies according to the pathological mechanism involved.
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Affiliation(s)
- He Cai
- Cardiovascular Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Hongbo Men
- Cardiovascular Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Pengyu Cao
- Cardiovascular Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yang Zheng
- Cardiovascular Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin 130021, P.R. China
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Hitawala G, Jain E, Castellanos L, Garimella R, Akku R, Chamavaliyathil AK, Irfan H, Jaiswal V, Quinonez J, Dakroub M, Hanif M, Baloch AH, Gomez IS, Dylewski J. Pediatric Chemotherapy Drugs Associated With Cardiotoxicity. Cureus 2021; 13:e19658. [PMID: 34976454 PMCID: PMC8679581 DOI: 10.7759/cureus.19658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2021] [Indexed: 11/05/2022] Open
Abstract
Pediatric cancers are a common cause of childhood morbidity. As a result, chemotherapeutic regimens have been designed to target childhood cancers. These medications are necessary to treat pediatric cancers, however, oncology management options are accompanied by multiple negative and potentially fatal adverse effects. Although anthracyclines are the most commonly used chemotherapeutic agents associated with cardiotoxicity, we also explore other chemotherapeutic drugs used in children that can potentially affect the heart. Genetic variations resulting in single nucleotide polymorphism (SNP) have the propensity to modify the cardiotoxic effects of the chemotherapy drugs. The clinical presentation of the cardiac effects can vary from arrhythmias and heart failure to completely asymptomatic. A range of imaging studies and laboratory investigations can protect the heart from severe outcomes. The physiology of the heart and the effect of drugs in children vary vividly from adults; therefore, it is crucial to study the cardiotoxic effect of chemotherapy drugs in the pediatric population. This review highlights the potential contributing factors for cardiotoxicity in the pediatric population and discusses the identification and management options.
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Affiliation(s)
- Gazala Hitawala
- Internal Medicine, Jersey City (JC) Medical Center, Orlando, USA
| | - Esha Jain
- Medicine, American University of Antigua, St. John's, ATG
| | | | | | - Radhika Akku
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Adila K Chamavaliyathil
- Pediatrics, Ras Al Khaimah (RAK) Medical and Health Sciences University, Ras Al Khaimah, ARE
| | - Huma Irfan
- Research, Larkin Community Hospital, South Miami, USA
| | | | - Jonathan Quinonez
- Neurology/Osteopathic Neuromuscular Medicine, Larkin Community Hospital, Miami, USA
| | - Maher Dakroub
- Hematology and Oncology, Larkin Community Hospital, South Miami, USA
| | - Muhammad Hanif
- Internal Medicine, Khyber Medical College Peshawar, Hayatabad Medical Complex, Peshawar, PAK
| | - Ali H Baloch
- Research, University of Maryland Medical Center, Baltimore, USA
| | - Ivan S Gomez
- Cardiology, Larkin Community Hospital, South Miami, USA
| | - John Dylewski
- Cardiology, Larkin Community Hospital, South Miami, USA
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13
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Jirkovský E, Jirkovská A, Bavlovič-Piskáčková H, Skalická V, Pokorná Z, Karabanovich G, Kollárová-Brázdová P, Kubeš J, Lenčová-Popelová O, Mazurová Y, Adamcová M, Lyon AR, Roh J, Šimůnek T, Štěrbová-Kovaříková P, Štěrba M. Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation. Circ Heart Fail 2021; 14:e008209. [PMID: 34551586 DOI: 10.1161/circheartfailure.120.008209] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Anthracycline-induced heart failure has been traditionally attributed to direct iron-catalyzed oxidative damage. Dexrazoxane (DEX)-the only drug approved for its prevention-has been believed to protect the heart via its iron-chelating metabolite ADR-925. However, direct evidence is lacking, and recently proposed TOP2B (topoisomerase II beta) hypothesis challenged the original concept. METHODS Pharmacokinetically guided study of the cardioprotective effects of clinically used DEX and its chelating metabolite ADR-925 (administered exogenously) was performed together with mechanistic experiments. The cardiotoxicity was induced by daunorubicin in neonatal ventricular cardiomyocytes in vitro and in a chronic rabbit model in vivo (n=50). RESULTS Intracellular concentrations of ADR-925 in neonatal ventricular cardiomyocytes and rabbit hearts after treatment with exogenous ADR-925 were similar or exceeded those observed after treatment with the parent DEX. However, ADR-925 did not protect neonatal ventricular cardiomyocytes against anthracycline toxicity, whereas DEX exhibited significant protective effects (10-100 µmol/L; P<0.001). Unlike DEX, ADR-925 also had no significant impact on daunorubicin-induced mortality, blood congestion, and biochemical and functional markers of cardiac dysfunction in vivo (eg, end point left ventricular fractional shortening was 32.3±14.7%, 33.5±4.8%, 42.7±1.0%, and 41.5±1.1% for the daunorubicin, ADR-925 [120 mg/kg]+daunorubicin, DEX [60 mg/kg]+daunorubicin, and control groups, respectively; P<0.05). DEX, but not ADR-925, inhibited and depleted TOP2B and prevented daunorubicin-induced genotoxic damage. TOP2B dependency of the cardioprotective effects was probed and supported by experiments with diastereomers of a new DEX derivative. CONCLUSIONS This study strongly supports a new mechanistic paradigm that attributes clinically effective cardioprotection against anthracycline cardiotoxicity to interactions with TOP2B but not metal chelation and protection against direct oxidative damage.
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Affiliation(s)
- Eduard Jirkovský
- Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic.,Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové (E.J.), Charles University, Czech Republic
| | - Anna Jirkovská
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové (A.J., V.S., J.K., T.Š.), Charles University, Czech Republic
| | - Hana Bavlovič-Piskáčková
- Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové (H.B.-P., P.Š.-K.), Charles University, Czech Republic
| | - Veronika Skalická
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové (A.J., V.S., J.K., T.Š.), Charles University, Czech Republic
| | - Zuzana Pokorná
- Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic
| | - Galina Karabanovich
- Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové (G.K., J.R.), Charles University, Czech Republic
| | - Petra Kollárová-Brázdová
- Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic
| | - Jan Kubeš
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové (A.J., V.S., J.K., T.Š.), Charles University, Czech Republic
| | - Olga Lenčová-Popelová
- Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic
| | - Yvona Mazurová
- Department of Histology and Embryology, Faculty of Medicine in Hradec Králové (Y.M.), Charles University, Czech Republic
| | - Michaela Adamcová
- Department of Physiology, Faculty of Medicine in Hradec Králové (M.A.), Charles University, Czech Republic
| | - Alexander R Lyon
- Department of Cardiology, Royal Brompton Hospital and Faculty of Medicine, National Heart and Lung Institute, Imperial College London, United Kingdom (A.R.L.)
| | - Jaroslav Roh
- Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové (G.K., J.R.), Charles University, Czech Republic
| | - Tomáš Šimůnek
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové (A.J., V.S., J.K., T.Š.), Charles University, Czech Republic
| | - Petra Štěrbová-Kovaříková
- Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové (H.B.-P., P.Š.-K.), Charles University, Czech Republic
| | - Martin Štěrba
- Department of Pharmacology, Faculty of Medicine in Hradec Králové (E.J., Z.P., P.K.-B., O.L.-P., M.Š.), Charles University, Czech Republic
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14
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Prodrug of ICRF-193 provides promising protective effects against chronic anthracycline cardiotoxicity in a rabbit model in vivo. Clin Sci (Lond) 2021; 135:1897-1914. [PMID: 34318878 DOI: 10.1042/cs20210311] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 11/17/2022]
Abstract
The anthracycline (ANT) anticancer drugs such as doxorubicin or daunorubicin (DAU) can cause serious myocardial injury and chronic cardiac dysfunction in cancer survivors. A bisdioxopiperazine agent dexrazoxane (DEX) has been developed as a cardioprotective drug to prevent these adverse events, but it is uncertain whether it is the best representative of the class. The present study used a rabbit model of chronic ANT cardiotoxicity to examine another bisdioxopiperazine compound called GK-667 (meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4,1-diyl))bis(methylene)-bis(2-aminoacetate) hydrochloride), a water-soluble prodrug of ICRF-193 (meso-4,4'-(butan-2,3-diyl)bis(piperazine-2,6-dione)), as a potential cardioprotectant. The cardiotoxicity was induced by DAU (3 mg/kg, intravenously, weekly, 10 weeks), and GK-667 (1 or 5 mg/kg, intravenously) was administered before each DAU dose. The treatment with GK-667 was well tolerated and provided full protection against DAU-induced mortality and left ventricular (LV) dysfunction (determined by echocardiography and LV catheterization). Markers of cardiac damage/dysfunction revealed minor cardiac damage in the group co-treated with GK-667 in the lower dose, whereas almost full protection was achieved with the higher dose. This was associated with similar prevention of DAU-induced dysregulation of redox and calcium homeostasis proteins. GK-667 dose-dependently prevented tumor suppressor p53 (p53)-mediated DNA damage response in the LV myocardium not only in the chronic experiment but also after single DAU administration. These effects appear essential for cardioprotection, presumably because of the topoisomerase IIβ (TOP2B) inhibition provided by its active metabolite ICRF-193. In addition, GK-667 administration did not alter the plasma pharmacokinetics of DAU and its main metabolite daunorubicinol (DAUol) in rabbits in vivo. Hence, GK-667 merits further investigation as a promising drug candidate for cardioprotection against chronic ANT cardiotoxicity.
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Jirkovská A, Karabanovich G, Kubeš J, Skalická V, Melnikova I, Korábečný J, Kučera T, Jirkovský E, Nováková L, Bavlovič Piskáčková H, Škoda J, Štěrba M, Austin CA, Šimůnek T, Roh J. Structure-Activity Relationship Study of Dexrazoxane Analogues Reveals ICRF-193 as the Most Potent Bisdioxopiperazine against Anthracycline Toxicity to Cardiomyocytes Due to Its Strong Topoisomerase IIβ Interactions. J Med Chem 2021; 64:3997-4019. [PMID: 33750129 DOI: 10.1021/acs.jmedchem.0c02157] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Cardioprotective activity of dexrazoxane (ICRF-187), the only clinically approved drug against anthracycline-induced cardiotoxicity, has traditionally been attributed to its iron-chelating metabolite. However, recent experimental evidence suggested that the inhibition and/or depletion of topoisomerase IIβ (TOP2B) by dexrazoxane could be cardioprotective. Hence, we evaluated a series of dexrazoxane analogues and found that their cardioprotective activity strongly correlated with their interaction with TOP2B in cardiomyocytes, but was independent of their iron chelation ability. Very tight structure-activity relationships were demonstrated on stereoisomeric forms of 4,4'-(butane-2,3-diyl)bis(piperazine-2,6-dione). In contrast to its rac-form 12, meso-derivative 11 (ICRF-193) showed a favorable binding mode to topoisomerase II in silico, inhibited and depleted TOP2B in cardiomyocytes more efficiently than dexrazoxane, and showed the highest cardioprotective efficiency. Importantly, the observed ICRF-193 cardioprotection did not interfere with the antiproliferative activity of anthracycline. Hence, this study identifies ICRF-193 as the new lead compound in the development of efficient cardioprotective agents.
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Affiliation(s)
- Anna Jirkovská
- Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic
| | - Galina Karabanovich
- Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic
| | - Jan Kubeš
- Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic
| | - Veronika Skalická
- Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic
| | - Iuliia Melnikova
- Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic
| | - Jan Korábečný
- Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Králové, Czech Republic
- Faculty of Military Health Sciences, University of Defence, Třebešská 1575, 50005 Hradec Králové, Czech Republic
| | - Tomáš Kučera
- Faculty of Military Health Sciences, University of Defence, Třebešská 1575, 50005 Hradec Králové, Czech Republic
| | - Eduard Jirkovský
- Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic
| | - Lucie Nováková
- Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic
| | - Hana Bavlovič Piskáčková
- Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic
| | - Josef Škoda
- Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic
| | - Martin Štěrba
- Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 50003 Hradec Králové, Czech Republic
| | - Caroline A Austin
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom
| | - Tomáš Šimůnek
- Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic
| | - Jaroslav Roh
- Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic
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16
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Bavlovič Piskáčková H, Jansová H, Kubeš J, Karabanovich G, Váňová N, Kollárová-Brázdová P, Melnikova I, Jirkovská A, Lenčová-Popelová O, Chládek J, Roh J, Šimůnek T, Štěrba M, Štěrbová-Kovaříková P. Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity. Sci Rep 2021; 11:4456. [PMID: 33627707 PMCID: PMC7904827 DOI: 10.1038/s41598-021-83688-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 01/01/2021] [Indexed: 02/06/2023] Open
Abstract
The bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical practice against anthracycline cardiotoxicity. However, the poor aqueous solubility of ICRF-193 has precluded its further in vivo development as a cardioprotective agent. To overcome this issue, water-soluble prodrugs of ICRF-193 were prepared, their abilities to release ICRF-193 were investigated using a novel UHPLC-MS/MS assay, and their cytoprotective effects against anthracycline cardiotoxicity were tested in vitro in neonatal ventricular cardiomyocytes (NVCMs). Based on the obtained results, the bis(2-aminoacetoxymethyl)-type prodrug GK-667 was selected for advanced investigations due to its straightforward synthesis, sufficient solubility, low cytotoxicity and favorable ICRF-193 release. Upon administration of GK-667 to NVCMs, the released ICRF-193 penetrated well into the cells, reached sufficient intracellular concentrations and provided effective cytoprotection against anthracycline toxicity. The pharmacokinetics of the prodrug, ICRF-193 and its rings-opened metabolite was estimated in vivo after administration of GK-667 to rabbits. The plasma concentrations of ICRF-193 reached were found to be adequate to achieve cardioprotective effects in vivo. Hence, GK-667 was demonstrated to be a pharmaceutically acceptable prodrug of ICRF-193 and a promising drug candidate for further evaluation as a potential cardioprotectant against chronic anthracycline toxicity.
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Affiliation(s)
- Hana Bavlovič Piskáčková
- Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
| | - Hana Jansová
- Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
| | - Jan Kubeš
- Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
| | - Galina Karabanovich
- Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
| | - Nela Váňová
- Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
| | - Petra Kollárová-Brázdová
- Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03, Hradec Králové, Czech Republic
| | - Iuliia Melnikova
- Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
| | - Anna Jirkovská
- Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
| | - Olga Lenčová-Popelová
- Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03, Hradec Králové, Czech Republic
| | - Jaroslav Chládek
- Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03, Hradec Králové, Czech Republic
| | - Jaroslav Roh
- Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
| | - Tomáš Šimůnek
- Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
| | - Martin Štěrba
- Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03, Hradec Králové, Czech Republic
| | - Petra Štěrbová-Kovaříková
- Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic.
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17
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Chan BYH, Roczkowsky A, Cho WJ, Poirier M, Sergi C, Keschrumrus V, Churko JM, Granzier H, Schulz R. MMP inhibitors attenuate doxorubicin cardiotoxicity by preventing intracellular and extracellular matrix remodelling. Cardiovasc Res 2021; 117:188-200. [PMID: 31995179 PMCID: PMC7797218 DOI: 10.1093/cvr/cvaa017] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 12/18/2019] [Accepted: 01/21/2020] [Indexed: 12/20/2022] Open
Abstract
AIMS Heart failure is a major complication in cancer treatment due to the cardiotoxic effects of anticancer drugs, especially from the anthracyclines such as doxorubicin (DXR). DXR enhances oxidative stress and stimulates matrix metalloproteinase-2 (MMP-2) in cardiomyocytes. We investigated whether MMP inhibitors protect against DXR cardiotoxicity given the role of MMP-2 in proteolyzing sarcomeric proteins in the heart and remodelling the extracellular matrix. METHODS AND RESULTS Eight-week-old male C57BL/6J mice were treated with DXR weekly with or without MMP inhibitors doxycycline or ONO-4817 by daily oral gavage for 4 weeks. Echocardiography was used to determine cardiac function and left ventricular remodelling before and after treatment. MMP inhibitors ameliorated DXR-induced systolic and diastolic dysfunction by reducing the loss in left ventricular ejection fraction, fractional shortening, and E'/A'. MMP inhibitors attenuated adverse left ventricular remodelling, reduced cardiomyocyte dropout, and prevented myocardial fibrosis. DXR increased myocardial MMP-2 activity in part also by upregulating N-terminal truncated MMP-2. Immunogold transmission electron microscopy showed that DXR elevated MMP-2 levels within the sarcomere and mitochondria which were associated with myofilament lysis, mitochondrial degeneration, and T-tubule distention. DXR-induced myofilament lysis was associated with increased titin proteolysis in the heart which was prevented by ONO-4817. DXR also increased the level and activity of MMP-2 in human embryonic stem cell-derived cardiomyocytes, which was reduced by ONO-4817. CONCLUSIONS MMP-2 activation is an early event in DXR cardiotoxicity and contributes to myofilament lysis by proteolyzing cardiac titin. Two orally available MMP inhibitors ameliorated DXR cardiotoxicity by attenuating intracellular and extracellular matrix remodelling, suggesting their use may be a potential prophylactic strategy to prevent heart injury during chemotherapy.
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Affiliation(s)
- Brandon Y H Chan
- Department of Pediatrics and Pharmacology, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - Andrej Roczkowsky
- Department of Pediatrics and Pharmacology, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - Woo Jung Cho
- Faculty of Medicine and Dentistry Cell Imaging Centre, University of Alberta, Edmonton, AB, Canada
| | - Mathieu Poirier
- Department of Pediatrics and Pharmacology, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - Consolato Sergi
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Vic Keschrumrus
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
| | - Jared M Churko
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
| | - Henk Granzier
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
| | - Richard Schulz
- Department of Pediatrics and Pharmacology, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB T6G 2S2, Canada
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18
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Abstract
The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanism of anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.
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19
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Kollárová-Brázdová P, Jirkovská A, Karabanovich G, Pokorná Z, Bavlovič Piskáčková H, Jirkovský E, Kubeš J, Lenčová-Popelová O, Mazurová Y, Adamcová M, Skalická V, Štěrbová-Kovaříková P, Roh J, Šimůnek T, Štěrba M. Investigation of Structure-Activity Relationships of Dexrazoxane Analogs Reveals Topoisomerase II β Interaction as a Prerequisite for Effective Protection against Anthracycline Cardiotoxicity. J Pharmacol Exp Ther 2020; 373:402-415. [PMID: 32253261 DOI: 10.1124/jpet.119.264580] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 03/23/2020] [Indexed: 01/23/2023] Open
Abstract
Bisdioxopiperazine agent dexrazoxane (ICRF-187) has been the only effective and approved drug for prevention of chronic anthracycline cardiotoxicity. However, the structure-activity relationships (SARs) of its cardioprotective effects remain obscure owing to limited investigation of its derivatives/analogs and uncertainties about its mechanism of action. To fill these knowledge gaps, we tested the hypothesis that dexrazoxane derivatives exert cardioprotection via metal chelation and/or modulation of topoisomerase IIβ (Top2B) activity in chronic anthracycline cardiotoxicity. Dexrazoxane was alkylated in positions that should not interfere with the metal-chelating mechanism of cardioprotective action; that is, on dioxopiperazine imides or directly on the dioxopiperazine ring. The protective effects of these agents were assessed in vitro in neonatal cardiomyocytes. All studied modifications of dexrazoxane molecule, including simple methylation, were found to abolish the cardioprotective effects. Because this challenged the prevailing mechanistic concept and previously reported data, the two closest derivatives [(±)-4,4'-(propane-1,2-diyl)bis(1-methylpiperazine-2,6-dione) and 4-(2-(3,5-dioxopiperazin-1-yl)ethyl)-3-methylpiperazine-2,6-dione] were thoroughly scrutinized in vivo using a rabbit model of chronic anthracycline cardiotoxicity. In contrast to dexrazoxane, both compounds failed to protect the heart, as demonstrated by mortality, cardiac dysfunction, and myocardial damage parameters, although the pharmacokinetics and metal-chelating properties of their metabolites were comparable to those of dexrazoxane. The loss of cardiac protection was shown to correlate with their abated potential to inhibit and deplete Top2B both in vitro and in vivo. These findings suggest a very tight SAR between bisdioxopiperazine derivatives and their cardioprotective effects and support Top2B as a pivotal upstream druggable target for effective cardioprotection against anthracycline cardiotoxicity. SIGNIFICANCE STATEMENT: This study has revealed the previously unexpected tight structure-activity relationships of cardioprotective effects in derivatives of dexrazoxane, which is the only drug approved for the prevention of cardiomyopathy and heart failure induced by anthracycline anticancer drugs. The data presented in this study also strongly argue against the importance of metal-chelating mechanisms for the induction of this effect and support the viability of topoisomerase IIβ as an upstream druggable target for effective and clinically translatable cardioprotection.
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Affiliation(s)
- Petra Kollárová-Brázdová
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Anna Jirkovská
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Galina Karabanovich
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Zuzana Pokorná
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Hana Bavlovič Piskáčková
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Eduard Jirkovský
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Jan Kubeš
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Olga Lenčová-Popelová
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Yvona Mazurová
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Michaela Adamcová
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Veronika Skalická
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Petra Štěrbová-Kovaříková
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Jaroslav Roh
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Tomáš Šimůnek
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Martin Štěrba
- Departments of Pharmacology (P.K.-B., Z.P., E.J., O.L.-P., M.Š.), Histology and Embryology (Y.M.), and Physiology (M.A.), Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; and Departments of Biochemical Sciences (A.J., J.K., V.S., T.Š.), Organic and Bioorganic Chemistry (G.K., J.R.), Pharmaceutical Chemistry and Pharmaceutical Analysis (H.B.P., P.Š.-K.), and Pharmacology and Toxicology (E.J.), Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Sobczuk P, Czerwińska M, Kleibert M, Cudnoch-Jędrzejewska A. Anthracycline-induced cardiotoxicity and renin-angiotensin-aldosterone system-from molecular mechanisms to therapeutic applications. Heart Fail Rev 2020; 27:295-319. [PMID: 32472524 PMCID: PMC8739307 DOI: 10.1007/s10741-020-09977-1] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Few millions of new cancer cases are diagnosed worldwide every year. Due to significant progress in understanding cancer biology and developing new therapies, the mortality rates are decreasing with many of patients that can be completely cured. However, vast majority of them require chemotherapy which comes with high medical costs in terms of adverse events, of which cardiotoxicity is one of the most serious and challenging. Anthracyclines (doxorubicin, epirubicin) are a class of cytotoxic agents used in treatment of breast cancer, sarcomas, or hematological malignancies that are associated with high risk of cardiotoxicity that is observed in even up to 30% of patients and can be diagnosed years after the therapy. The mechanism, in which anthracyclines cause cardiotoxicity are not well known, but it is proposed that dysregulation of renin-angiotensin-aldosterone system (RAAS), one of main humoral regulators of cardiovascular system, may play a significant role. There is increasing evidence that drugs targeting this system can be effective in the prevention and treatment of anthracycline-induced cardiotoxicity what has recently found reflection in the recommendation of some scientific societies. In this review, we comprehensively describe possible mechanisms how anthracyclines affect RAAS and lead to cardiotoxicity. Moreover, we critically review available preclinical and clinical data on use of RAAS inhibitors in the primary and secondary prevention and treatment of cardiac adverse events associated with anthracycline-based chemotherapy.
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Affiliation(s)
- Paweł Sobczuk
- Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland.,Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Magdalena Czerwińska
- Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Marcin Kleibert
- Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Agnieszka Cudnoch-Jędrzejewska
- Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland.
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21
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Rocca C, Pasqua T, Cerra MC, Angelone T. Cardiac Damage in Anthracyclines Therapy: Focus on Oxidative Stress and Inflammation. Antioxid Redox Signal 2020; 32:1081-1097. [PMID: 31928066 DOI: 10.1089/ars.2020.8016] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Despite their serious side effects, anthracyclines (ANTs) are the most prescribed chemotherapeutic drugs because of their strong efficacy in both solid and hematological tumors. A major limitation to ANTs clinical application is the severe cardiotoxicity observed both acutely and chronically. The mechanism underlying cardiac dysfunction under chemotherapy is mainly dependent on the generation of oxidative stress and systemic inflammation, both of which lead to progressive cardiomyopathy and heart failure. Recent Advances: Over the years, the iatrogenic ANTs-induced cardiotoxicity was believed to be simply given by iron metabolism and reactive oxygen species production; however, several experimental data indicate that ANTs may use alternative damaging mechanisms, such as topoisomerase 2β inhibition, inflammation, pyroptosis, immunometabolism, and autophagy. Critical Issues: In this review, we aimed at discussing ANTs-induced cardiac injury from different points of view, updating and focusing on oxidative stress and inflammation, since these pathways are not exclusive or independent from each other but they together importantly contribute to the complexity of ANTs-induced multifactorial cardiotoxicity. Future Directions: A deeper understanding of the mechanistic signaling leading to ANTs side effects could reveal crucial targeting molecules, thus representing strategic knowledge to promote better therapeutic efficacy and lower cardiotoxicity during clinical application.
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Affiliation(s)
- Carmine Rocca
- Laboratory of Cellular and Molecular Cardiovascular Physiology, Department of Biology, Ecology and Earth Sciences, University of Calabria, Rende, Italy
| | - Teresa Pasqua
- Laboratory of Cellular and Molecular Cardiovascular Physiology, Department of Biology, Ecology and Earth Sciences, University of Calabria, Rende, Italy
| | - Maria Carmela Cerra
- Laboratory of Organ and System Physiology, Department of Biology, Ecology and Earth Sciences, University of Calabria, Rende, Italy.,National Institute of Cardiovascular Research (INRC), Bologna, Italy
| | - Tommaso Angelone
- Laboratory of Cellular and Molecular Cardiovascular Physiology, Department of Biology, Ecology and Earth Sciences, University of Calabria, Rende, Italy.,National Institute of Cardiovascular Research (INRC), Bologna, Italy
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22
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Takaguri A, Akihiro O, Sasano J, Satoh K. Involvement of Yes-associated protein 1 (YAP1) in doxorubicin-induced cytotoxicity in H9c2 cardiac cells. Cell Biol Int 2019; 44:873-881. [PMID: 31833156 DOI: 10.1002/cbin.11285] [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: 09/01/2019] [Accepted: 12/10/2019] [Indexed: 11/06/2022]
Abstract
Cardiac cell death is one of the major events implicated in doxorubicin-induced cardiotoxicity, which leads to heart failure. We recently reported that Yes-associated protein 1 (YAP1) regulates cell survival and apoptosis. However, it is unclear whether YAP1 regulates doxorubicin-induced cell death in cardiomyocytes. We investigated whether YAP1 is involved in doxorubicin-induced cell death using H9c2 cardiac cells and mouse heart. In an in vivo study, YAP1 protein expression was significantly decreased in hearts of doxorubicin-treated mice with increased caspase-3 activation. Doxorubicin also caused cell death by increasing caspase-3 activation in H9c2 cells. Doxorubicin reduced YAP1 protein expression and messenger RNA expression accompanied by increased phosphorylation of YAP1 at Ser127. Doxorubicin further increased cell death with increased caspase-3/7 activation in the absence of YAP1 when compared with doxorubicin or siYAP1 treatment alone. Overexpression of constitutively active YAP1 (YAP1-5SA) using an adenovirus gene transfer technique significantly reversed doxorubicin-induced cell death by decreasing caspase-3/7 activation in H9c2 cells. Akt, a potential prosurvival factor, decreased in doxorubicin- and YAP1 short interfering RNA (siRNA)-treated cells. Doxorubicin further significantly decreased Akt protein expression when YAP1 was silenced. Overexpression of YAP1 canceled decreased Akt protein expression induced by doxorubicin treatment in H9c2 cells. In conclusion, these results suggest that doxorubicin-induced cardiac cell death is mediated in part by down-regulation of YAP1 and YAP1-targeted gene, Akt. Modulating YAP1 and its related Hippo pathway on local cardiomyocytes may be a promising therapeutic approach for doxorubicin-induced cardiotoxicity.
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Affiliation(s)
- Akira Takaguri
- Department of Pharmacology, Hokkaido University of Science, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan
| | - Ohmiya Akihiro
- Department of Pharmacology, Hokkaido University of Science, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan
| | - Jun Sasano
- Department of Pharmacology, Hokkaido University of Science, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan
| | - Kumi Satoh
- Department of Pharmacology, Hokkaido University of Science, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan
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23
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Tocchetti CG, Cadeddu C, Di Lisi D, Femminò S, Madonna R, Mele D, Monte I, Novo G, Penna C, Pepe A, Spallarossa P, Varricchi G, Zito C, Pagliaro P, Mercuro G. From Molecular Mechanisms to Clinical Management of Antineoplastic Drug-Induced Cardiovascular Toxicity: A Translational Overview. Antioxid Redox Signal 2019; 30:2110-2153. [PMID: 28398124 PMCID: PMC6529857 DOI: 10.1089/ars.2016.6930] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Significance: Antineoplastic therapies have significantly improved the prognosis of oncology patients. However, these treatments can bring to a higher incidence of side-effects, including the worrying cardiovascular toxicity (CTX). Recent Advances: Substantial evidence indicates multiple mechanisms of CTX, with redox mechanisms playing a key role. Recent data singled out mitochondria as key targets for antineoplastic drug-induced CTX; understanding the underlying mechanisms is, therefore, crucial for effective cardioprotection, without compromising the efficacy of anti-cancer treatments. Critical Issues: CTX can occur within a few days or many years after treatment. Type I CTX is associated with irreversible cardiac cell injury, and it is typically caused by anthracyclines and traditional chemotherapeutics. Type II CTX is generally caused by novel biologics and more targeted drugs, and it is associated with reversible myocardial dysfunction. Therefore, patients undergoing anti-cancer treatments should be closely monitored, and patients at risk of CTX should be identified before beginning treatment to reduce CTX-related morbidity. Future Directions: Genetic profiling of clinical risk factors and an integrated approach using molecular, imaging, and clinical data may allow the recognition of patients who are at a high risk of developing chemotherapy-related CTX, and it may suggest methodologies to limit damage in a wider range of patients. The involvement of redox mechanisms in cancer biology and anticancer treatments is a very active field of research. Further investigations will be necessary to uncover the hallmarks of cancer from a redox perspective and to develop more efficacious antineoplastic therapies that also spare the cardiovascular system.
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Affiliation(s)
| | - Christian Cadeddu
- 2 Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Daniela Di Lisi
- 3 Biomedical Department of Internal Medicine, University of Palermo, Palermo, Italy
| | - Saveria Femminò
- 4 Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Rosalinda Madonna
- 5 Center of Aging Sciences and Translational Medicine - CESI-MeT, "G. d'Annunzio" University, Chieti, Italy.,6 Department of Internal Medicine, The Texas Heart Institute and Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Donato Mele
- 7 Cardiology Unit, Emergency Department, University Hospital of Ferrara, Ferrara, Italy
| | - Ines Monte
- 8 Department of General Surgery and Medical-Surgery Specialities, University of Catania, Catania, Italy
| | - Giuseppina Novo
- 3 Biomedical Department of Internal Medicine, University of Palermo, Palermo, Italy
| | - Claudia Penna
- 4 Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Alessia Pepe
- 9 U.O.C. Magnetic Resonance Imaging, Fondazione Toscana G. Monasterio C.N.R., Pisa, Italy
| | - Paolo Spallarossa
- 10 Clinic of Cardiovascular Diseases, IRCCS San Martino IST, Genova, Italy
| | - Gilda Varricchi
- 1 Department of Translational Medical Sciences, Federico II University, Naples, Italy.,11 Center for Basic and Clinical Immunology Research (CISI) - Federico II University, Naples, Italy
| | - Concetta Zito
- 12 Division of Cardiology, Clinical and Experimental Department of Medicine and Pharmacology, Policlinico "G. Martino" University of Messina, Messina, Italy
| | - Pasquale Pagliaro
- 4 Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Giuseppe Mercuro
- 2 Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
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Abstract
Doxorubicin-induced cardiotoxicity in childhood cancer survivors is a growing problem. The population of patients at risk for cardiovascular disease is steadily increasing, as five-year survival rates for all types of childhood cancers continue to improve. Doxorubicin affects the developing heart differently from the adult heart and in a subset of exposed patients, childhood exposure leads to late, irreversible cardiomyopathy. Notably, the prevalence of late-onset toxicity is increasing in parallel with improved survival. By the year 2020, it is estimated that there will be 500,000 childhood cancer survivors and over 50,000 of them will suffer from doxorubicin-induced cardiotoxicity. The majority of the research to-date, concentrated on childhood cancer survivors, has focused mostly on clinical outcomes through well-designed epidemiological and retrospective cohort studies. Preclinical studies have elucidated many of the cellular mechanisms that elicit acute toxicity in cardiomyocytes. However, more research is needed in the areas of early- and late-onset cardiotoxicity and more importantly improving the scientific understanding of how other cells present in the cardiac milieu are impacted by doxorubicin exposure. The overall goal of this review is to succinctly summarize the major clinical and preclinical studies focused on doxorubicin-induced cardiotoxicity. As the prevalence of patients affected by doxorubicin exposure continues to increase, it is imperative that the major gaps in existing research are identified and subsequently utilized to develop appropriate research priorities for the coming years. Well-designed preclinical research models will enhance our understanding of the pathophysiology of doxorubicin-induced cardiotoxicity and directly lead to better diagnosis, treatment, and prevention. © 2019 American Physiological Society. Compr Physiol 9:905-931, 2019.
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Affiliation(s)
- Trevi R. Mancilla
- University of Texas Health Science Center San Antonio, San Antonio, Texas, USA
| | - Brian Iskra
- University of Texas Health Science Center San Antonio, San Antonio, Texas, USA
| | - Gregory J. Aune
- University of Texas Health Science Center San Antonio, San Antonio, Texas, USA
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25
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Bertero E, Ameri P, Maack C. Bidirectional Relationship Between Cancer and Heart Failure: Old and New Issues in Cardio-oncology. Card Fail Rev 2019; 5:106-111. [PMID: 31179021 PMCID: PMC6546001 DOI: 10.15420/cfr.2019.1.2] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 02/14/2019] [Indexed: 02/07/2023] Open
Abstract
The main focus of cardio-oncology has been the prevention and treatment of the cardiac toxicity of chemotherapy and radiotherapy. Furthermore, several targeted therapies have been associated with unexpected cardiotoxic side-effects. Recently, epidemiological studies reported a higher incidence of cancer in patients with heart failure (HF) compared with individuals without HF. On this basis, it has been proposed that HF might represent an oncogenic condition. This hypothesis is supported by preclinical studies demonstrating that hyperactivation of the sympathetic nervous system and renin-angiotensin-aldosterone system, which is a hallmark of HF, promotes cancer growth and dissemination. Another intriguing possibility is that the co-occurrence of HF and cancer is promoted by a common pathological milieu characterised by a state of chronic low-grade inflammation, which predisposes to both diseases. In this review, we provide an overview of the mechanisms underlying the bidirectional relationship between HF and cancer.
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Affiliation(s)
- Edoardo Bertero
- Comprehensive Heart Failure Center, University Clinic Würzburg Würzburg, Germany
| | - Pietro Ameri
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino - IRCCS Italian Cardiovascular Network Genova, Italy.,Department of Internal Medicine and Centre of Excellence for Biomedical Research, University of Genova Genova, Italy
| | - Christoph Maack
- Comprehensive Heart Failure Center, University Clinic Würzburg Würzburg, Germany
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Ganatra S, Nohria A, Shah S, Groarke JD, Sharma A, Venesy D, Patten R, Gunturu K, Zarwan C, Neilan TG, Barac A, Hayek SS, Dani S, Solanki S, Mahmood SS, Lipshultz SE. Upfront dexrazoxane for the reduction of anthracycline-induced cardiotoxicity in adults with preexisting cardiomyopathy and cancer: a consecutive case series. CARDIO-ONCOLOGY (LONDON, ENGLAND) 2019; 5:1. [PMID: 32154008 PMCID: PMC7048095 DOI: 10.1186/s40959-019-0036-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 01/20/2019] [Indexed: 01/09/2023]
Abstract
BACKGROUND Cardiotoxicity associated with anthracycline-based chemotherapies has limited their use in patients with preexisting cardiomyopathy or heart failure. Dexrazoxane protects against the cardiotoxic effects of anthracyclines, but in the USA and some European countries, its use had been restricted to adults with advanced breast cancer receiving a cumulative doxorubicin (an anthracycline) dose > 300 mg/m2. We evaluated the off-label use of dexrazoxane as a cardioprotectant in adult patients with preexisting cardiomyopathy, undergoing anthracycline chemotherapy. METHODS Between July 2015 and June 2017, five consecutive patients, with preexisting, asymptomatic, systolic left ventricular (LV) dysfunction who required anthracycline-based chemotherapy, were concomitantly treated with off-label dexrazoxane, administered 30 min before each anthracycline dose, regardless of cancer type or stage. Demographic, cardiovascular, and cancer-related outcomes were compared to those of three consecutive patients with asymptomatic cardiomyopathy treated earlier at the same hospital without dexrazoxane. RESULTS Mean age of the five dexrazoxane-treated patients and three patients treated without dexrazoxane was 70.6 and 72.6 years, respectively. All five dexrazoxane-treated patients successfully completed their planned chemotherapy (doxorubicin, 280 to 300 mg/m2). With dexrazoxane therapy, changes in LV systolic function were minimal with mean left ventricular ejection fraction (LVEF) decreasing from 39% at baseline to 34% after chemotherapy. None of the dexrazoxane-treated patients experienced symptomatic heart failure or elevated biomarkers (cardiac troponin I or brain natriuretic peptide). Of the three patients treated without dexrazoxane, two received doxorubicin (mean dose, 210 mg/m2), and one received daunorubicin (540 mg/m2). Anthracycline therapy resulted in a marked reduction in LVEF from 42.5% at baseline to 18%. All three developed symptomatic heart failure requiring hospitalization and intravenous diuretic therapy. Two of them died from cardiogenic shock and multi-organ failure. CONCLUSION The concomitant administration of dexrazoxane in patients with preexisting cardiomyopathy permitted successful delivery of anthracycline-based chemotherapy without cardiac decompensation. Larger prospective trials are warranted to examine the use of dexrazoxane as a cardioprotectant in patients with preexisting cardiomyopathy who require anthracyclines.
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Affiliation(s)
- Sarju Ganatra
- Cardio-Oncology Program, Lahey Hospital and Medical Center, Burlington, MA USA
- Department of Cardiovascular Medicine, Lahey Hospital and Medical Center, Burlington, MA USA
- Cardio-Oncology Program, Department of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA USA
| | - Anju Nohria
- Cardio-Oncology Program, Department of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA USA
| | - Sachin Shah
- Department of Cardiovascular Medicine, Lahey Hospital and Medical Center, Burlington, MA USA
| | - John D. Groarke
- Cardio-Oncology Program, Department of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA USA
| | - Ajay Sharma
- Department of Cardiovascular Medicine, Lahey Hospital and Medical Center, Burlington, MA USA
| | - David Venesy
- Department of Cardiovascular Medicine, Lahey Hospital and Medical Center, Burlington, MA USA
| | - Richard Patten
- Department of Cardiovascular Medicine, Lahey Hospital and Medical Center, Burlington, MA USA
| | - Krishna Gunturu
- Department of Hematology Oncology, Lahey Hospital and Medical Center, Burlington, MA USA
- Cancer Survivorship Program, Lahey Hospital and Medical Center, Burlington, MA USA
| | - Corrine Zarwan
- Department of Hematology Oncology, Lahey Hospital and Medical Center, Burlington, MA USA
| | - Tomas G. Neilan
- Cardio-Oncology Program, Division of Cardiology, Massachusetts General Hospital, Boston, MA USA
| | - Ana Barac
- Cardio-Oncology Program, Division of Cardiology, Medstar Washington Hospital Center, Washington, DC USA
| | - Salim S. Hayek
- Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI USA
| | - Sourbha Dani
- Division of Cardiovascular Medicine, Eastern Maine Medical Center, Bangor, ME USA
| | - Shantanu Solanki
- Department of Medicine, Westchester Medical Center, Valhalla, NY USA
| | - Syed Saad Mahmood
- Division of Cardiovascular Medicine, New-York Presbyterian Hospital/Weill Cornell Medical Center, New York City, NY USA
| | - Steven E. Lipshultz
- Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Oishei Children’s Hospital, Roswell Park Comprehensive Cancer Center, Buffalo, NY USA
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27
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Abstract
Heart failure and breast cancer have shared risks and morbidities. Multimodality therapies for breast cancer, including conventional chemotherapy, targeted therapeutics, radiation therapy, and hormonal agents, may make patients more susceptible to asymptomatic left ventricular dysfunction and clinical heart failure during and after treatment. New or preexisting left ventricular dysfunction may lead to interruptions in cancer treatment and limit options of breast cancer systemic therapy, leading to adverse outcomes. Early recognition and management of cardiovascular risk factors before, during, and after cancer treatment are of utmost importance. This review presents advances, challenges, and opportunities for cardiovascular care in contemporary breast cancer treatment.
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Affiliation(s)
- Zakaria Almuwaqqat
- Department of Cardiology, Emory University School of Medicine, 1364 Clifton Road, Atlanta, GA 30322, USA; Rollins School of Public Health, Emory University, Atlanta, GA, USA.
| | - Jane L Meisel
- Department of Hematology and Medical Oncology, Emory University School of Medicine, 1364 Clifton Road, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, 1365 Clifton Road Atlanta, GA 30322, USA
| | - Ana Barac
- MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, 3800 Reservoir Road NW, Washington, DC 20007, USA; Department of Oncology, Georgetown University, 3800 Reservoir Road NW, Washington, DC 20007, USA
| | - Susmita Parashar
- Department of Cardiology, Emory University School of Medicine, 1364 Clifton Road, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, 1365 Clifton Road Atlanta, GA 30322, USA
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28
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Chan BYH, Roczkowsky A, Moser N, Poirier M, Hughes BG, Ilarraza R, Schulz R. Doxorubicin induces de novo expression of N-terminal-truncated matrix metalloproteinase-2 in cardiac myocytes. Can J Physiol Pharmacol 2018; 96:1238-1245. [PMID: 30308129 DOI: 10.1139/cjpp-2018-0275] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Anthracyclines, such as doxorubicin, are commonly prescribed antineoplastic agents that cause irreversible cardiac injury. Doxorubicin cardiotoxicity is initiated by increased oxidative stress in cardiomyocytes. Oxidative stress enhances intracellular matrix metalloproteinase-2 (MMP-2) by direct activation of its full-length isoform and (or) de novo expression of an N-terminal-truncated isoform (NTT-MMP-2). As MMP-2 is localized to the sarcomere, we tested whether doxorubicin activates intracellular MMP-2 in neonatal rat ventricular myocytes (NRVM) and whether it thereby proteolyzes two of its identified sarcomeric targets, α-actinin and troponin I. Doxorubicin increased oxidative stress within 12 h as indicated by reduced aconitase activity. This was associated with a twofold increase in MMP-2 protein levels and threefold higher gelatinolytic activity. MMP inhibitors ARP-100 or ONO-4817 (1 μM) prevented doxorubicin-induced MMP-2 activation. Doxorubicin also increased the levels and activity of MMP-2 secreted into the conditioned media. Doxorubicin upregulated the mRNA expression of both full-length MMP-2 and NTT-MMP-2. α-Actinin levels remained unchanged, whereas doxorubicin downregulated troponin I in an MMP-independent manner. Doxorubicin induces oxidative stress and stimulates a robust increase in MMP-2 expression and activity in NRVM, including NTT-MMP-2. The sarcomeric proteins α-actinin and troponin I are, however, not targeted by MMP-2 under these conditions.
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Affiliation(s)
- Brandon Y H Chan
- Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada.,Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - Andrej Roczkowsky
- Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada.,Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - Nils Moser
- Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada.,Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - Mathieu Poirier
- Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada.,Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - Bryan G Hughes
- Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada.,Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - Ramses Ilarraza
- Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada.,Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - Richard Schulz
- Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada.,Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada
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29
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Pillai VB, Kanwal A, Fang YH, Sharp WW, Samant S, Arbiser J, Gupta MP. Honokiol, an activator of Sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice. Oncotarget 2018; 8:34082-34098. [PMID: 28423723 PMCID: PMC5470953 DOI: 10.18632/oncotarget.16133] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 02/27/2017] [Indexed: 12/30/2022] Open
Abstract
Doxorubicin is the chemotherapeutic drug of choice for a wide variety of cancers, and cardiotoxicity is one of the major side effects of doxorubicin treatment. One of the main cellular targets of doxorubicin in the heart is mitochondria. Mitochondrial sirtuin, SIRT3 has been shown to protect against doxorubicin-induced cardiotoxicity. We have recently identified honokiol (HKL) as an activator of SIRT3, which protects the heart from developing pressure overload hypertrophy. Here, we show that HKL-mediated activation of SIRT3 also protects the heart from doxorubicin-induced cardiac damage without compromising the tumor killing potential of doxorubicin. Doxorubicin-induced cardiotoxicity is associated with increased ROS production and consequent fragmentation of mitochondria and cell death. HKL-mediated activation of SIRT3 prevented Doxorubicin induced ROS production, mitochondrial damage and cell death in rat neonatal cardiomyocytes. HKL also promoted mitochondrial fusion. We also show that treatment with HKL blocked doxorubicin-induced cardiac toxicity in mice. This was associated with reduced mitochondrial DNA damage and improved mitochondrial function. Furthermore, treatments of mice, bearing prostrate tumor-xenografts, with HKL and doxorubicin showed inhibition of tumor growth with significantly reduced cardiac toxicity. Our results suggest that HKL-mediated activation of SIRT3 protects the heart from doxorubicin-induced cardiotoxicity and represents a potentially novel adjunct for chemotherapy treatments.
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Affiliation(s)
- Vinodkumar B Pillai
- Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA
| | - Abhinav Kanwal
- Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA
| | - Yong Hu Fang
- Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA
| | - Willard W Sharp
- Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA
| | - Sadhana Samant
- Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA
| | - Jack Arbiser
- Department of Dermatology, Atlanta Veterans Administration Health Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Mahesh P Gupta
- Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA
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30
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Varricchi G, Ameri P, Cadeddu C, Ghigo A, Madonna R, Marone G, Mercurio V, Monte I, Novo G, Parrella P, Pirozzi F, Pecoraro A, Spallarossa P, Zito C, Mercuro G, Pagliaro P, Tocchetti CG. Antineoplastic Drug-Induced Cardiotoxicity: A Redox Perspective. Front Physiol 2018; 9:167. [PMID: 29563880 PMCID: PMC5846016 DOI: 10.3389/fphys.2018.00167] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 02/20/2018] [Indexed: 12/28/2022] Open
Abstract
Antineoplastic drugs can be associated with several side effects, including cardiovascular toxicity (CTX). Biochemical studies have identified multiple mechanisms of CTX. Chemoterapeutic agents can alter redox homeostasis by increasing the production of reactive oxygen species (ROS) and reactive nitrogen species RNS. Cellular sources of ROS/RNS are cardiomyocytes, endothelial cells, stromal and inflammatory cells in the heart. Mitochondria, peroxisomes and other subcellular components are central hubs that control redox homeostasis. Mitochondria are central targets for antineoplastic drug-induced CTX. Understanding the mechanisms of CTX is fundamental for effective cardioprotection, without compromising the efficacy of anticancer treatments. Type 1 CTX is associated with irreversible cardiac cell injury and is typically caused by anthracyclines and conventional chemotherapeutic agents. Type 2 CTX, associated with reversible myocardial dysfunction, is generally caused by biologicals and targeted drugs. Although oxidative/nitrosative reactions play a central role in CTX caused by different antineoplastic drugs, additional mechanisms involving directly and indirectly cardiomyocytes and inflammatory cells play a role in cardiovascular toxicities. Identification of cardiologic risk factors and an integrated approach using molecular, imaging, and clinical data may allow the selection of patients at risk of developing chemotherapy-related CTX. Although the last decade has witnessed intense research related to the molecular and biochemical mechanisms of CTX of antineoplastic drugs, experimental and clinical studies are urgently needed to balance safety and efficacy of novel cancer therapies.
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Affiliation(s)
- Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
- Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research, University of Naples Federico II, Naples, Italy
| | - Pietro Ameri
- Clinic of Cardiovascular Diseases, IRCCS San Martino IST, Genova, Italy
| | - Christian Cadeddu
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Alessandra Ghigo
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Rosalinda Madonna
- Institute of Cardiology, Center of Excellence on Aging, Università degli Studi “G. d'Annunzio” Chieti – Pescara, Chieti, Italy
- Department of Internal Medicine, Texas Heart Institute and Center for Cardiovascular Biology and Atherosclerosis Research, University of Texas Health Science Center, Houston, TX, United States
| | - Giancarlo Marone
- Section of Hygiene, Department of Public Health, University of Naples Federico II, Naples, Italy
- Monaldi Hospital Pharmacy, Naples, Italy
| | - Valentina Mercurio
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Ines Monte
- Department of General Surgery and Medical-Surgery Specialities, University of Catania, Catania, Italy
| | - Giuseppina Novo
- U.O.C. Magnetic Resonance Imaging, Fondazione Toscana G. Monasterio C.N.R., Pisa, Italy
| | - Paolo Parrella
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Flora Pirozzi
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Antonio Pecoraro
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Paolo Spallarossa
- Clinic of Cardiovascular Diseases, IRCCS San Martino IST, Genova, Italy
| | - Concetta Zito
- Division of Clinical and Experimental Cardiology, Department of Medicine and Pharmacology, Policlinico “G. Martino” University of Messina, Messina, Italy
| | - Giuseppe Mercuro
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Pasquale Pagliaro
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Carlo G. Tocchetti
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
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31
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Protective Effects of ω-3 PUFA in Anthracycline-Induced Cardiotoxicity: A Critical Review. Int J Mol Sci 2017; 18:ijms18122689. [PMID: 29231904 PMCID: PMC5751291 DOI: 10.3390/ijms18122689] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 11/29/2017] [Accepted: 12/08/2017] [Indexed: 12/31/2022] Open
Abstract
It has been demonstrated that ω-3 polyunsaturated fatty acids (ω-3 PUFA) may exert a beneficial role as adjuvants in the prevention and treatment of many disorders, including cardiovascular diseases and cancer. Particularly, several in vitro and in vivo preclinical studies have shown the antitumor activity of ω-3 PUFA in different kinds of cancers, and several human studies have shown that ω-3 PUFA are able to decrease the risk of a series of cardiovascular diseases. Several mechanisms have been proposed to explain their pleiotropic beneficial effects. ω-3 PUFA have also been shown to prevent harmful side-effects (including cardiotoxicity and heart failure) induced by conventional and innovative anti-cancer drugs in both animals and patients. The available literature regarding the possible protective effects of ω-3 PUFA against anthracycline-induced cardiotoxicity, as well as the mechanisms involved, will be critically discussed herein. The study will analyze the critical role of different levels of ω-3 PUFA intake in determining the results of the combinatory studies with anthracyclines. Suggestions for future research will also be considered.
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32
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Bures J, Jirkovska A, Sestak V, Jansova H, Karabanovich G, Roh J, Sterba M, Simunek T, Kovarikova P. Investigation of novel dexrazoxane analogue JR-311 shows significant cardioprotective effects through topoisomerase IIbeta but not its iron chelating metabolite. Toxicology 2017; 392:1-10. [PMID: 28941780 DOI: 10.1016/j.tox.2017.09.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 09/10/2017] [Accepted: 09/19/2017] [Indexed: 12/31/2022]
Abstract
Novel dexrazoxane derivative JR-311 was prepared to investigate structure-activity relationships and mechanism(s) of protection against anthracycline cardiotoxicity. Its cardioprotective, antiproliferative, iron (Fe) chelation and inhibitory and/or depletory activities on topoisomerase IIbeta (TOP2B) were examined and compared with dexrazoxane. While in standard assay, JR-311 failed in both cardioprotection and depletion of TOP2B, its repeated administration to cell culture media led to depletion of TOP2B and significant protection of isolated rat neonatal ventricular cardiomyocytes from daunorubicin-induced damage. This effect was explained by a focused analytical investigation that revealed rapid JR-311 decomposition, resulting in negligible intracellular concentrations of the parent compound but high exposure of cells to the decomposition products, including Fe-chelating JR-H2. Although chemical instability is an obstacle for the development of JR-311, this study identified a novel dexrazoxane analogue with preserved pharmacodynamic properties, contributed to the investigation of structure-activity relationships and suggested that the cardioprotection of bis-dioxopiperazines is likely attributed to TOP2B activity of the parent compound rather than Fe chelation of their hydrolytic metabolites/degradation products. Moreover, this study highlights the importance of early stability testing during future development of novel dexrazoxane analogues.
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Affiliation(s)
- Jan Bures
- Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
| | - Anna Jirkovska
- Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
| | - Vit Sestak
- Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
| | - Hana Jansova
- Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
| | - Galina Karabanovich
- Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
| | - Jaroslav Roh
- Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
| | - Martin Sterba
- Faculty of Medicine in Hradec Králové, Charles University, Šimkova 850, 500 03 Hradec Králové, Czech Republic
| | - Tomas Simunek
- Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
| | - Petra Kovarikova
- Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
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33
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Precision cardio-oncology: understanding the cardiotoxicity of cancer therapy. NPJ Precis Oncol 2017; 1:31. [PMID: 29872712 PMCID: PMC5871905 DOI: 10.1038/s41698-017-0034-x] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 07/29/2017] [Accepted: 08/01/2017] [Indexed: 12/21/2022] Open
Abstract
Current oncologic treatments have brought a strong reduction in mortality in cancer patients. However, the cancer therapy-related cardiovascular complications, in particular chemo-therapy and radiation therapy-induced cardiotoxicities are a major cause of morbidity and mortality in people living with or surviving cancer. The simple fact is that all antineoplastic agents and radiation therapy target tumor cells but also result in collateral damage to other tissues including the cardiovascular system. The commonly used anthracycline chemotherapy agents can induce cardiomyopathy and congestive heart failure. Targeted therapies with human epidermal growth factor antibodies, tyrosine kinase inhibitors or vascular endothelial growth factor antibodies, and the antimetabolites also have shown to induce cardiomyopathy and myocardial ischemia. Cardiac arrhythmias and hypertension have been well described with the use of tyrosine kinase inhibitors and antimicrotubule agents. Pericarditis can happen with the use of cyclophosphamide or cytarabine. Mediastinal radiation can cause constrictive pericarditis, myocardial fibrosis, valvular lesions, and coronary artery disease. Despite significant progresses in the understanding of the molecular and pathophysiologic mechanisms behind the cardiovascular toxicity of cancer therapy, there is still lack of evidence-based approach for the monitoring and management of patients. This review will focus mainly on the recent advances in the molecular mechanisms of cardiotoxicity related to common cancer therapies while introducing the concept of cardio-oncology service. Applying the general principles of multi-disciplinary approaches toward the diagnosis, prevention, monitoring, and treatment of cancer therapy-induced cardiomyopathy and heart failure will also be discussed.
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34
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Nima ZA, Alwbari AM, Dantuluri V, Hamzah RN, Sra N, Motwani P, Arnaoutakis K, Levy RA, Bohliqa AF, Nedosekin D, Zharov VP, Makhoul I, Biris AS. Targeting nano drug delivery to cancer cells using tunable, multi-layer, silver-decorated gold nanorods. J Appl Toxicol 2017; 37:1370-1378. [PMID: 28730725 DOI: 10.1002/jat.3495] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Revised: 05/14/2017] [Accepted: 05/16/2017] [Indexed: 12/21/2022]
Abstract
Multifunctional nanoparticles have high potential as targeting delivery vehicles for cancer chemotherapy. In this study, silver-decorated gold nanorods (AuNR\Ag) have been successfully used to deliver specific, targeted chemotherapy against breast cancer (MCF7) and prostate carcinoma (PC3) cell lines. Doxorubicin, a commonly used chemotherapy, and anti-Epithelial cell adhesion molecule (anti-EpCAM) antibodies were covalently bonded to thiolated polyethylene glycol-coated AuNR\Ag, and the resultant system was used to deliver the drugs to cancer cells in vitro. Furthermore, these nanoparticles have a unique spectral signature by surface enhanced Raman spectroscopy (SERS), which enables reliable detection and monitoring of the distribution of these chemotherapy constructs inside cells. The development of interest in a plasmonic nano drugs system with unique spectroscopic signatures could result in a clinical approach to the precise targeting and visualization of cells and solid tumors while delivering molecules for the enhanced treatment of cancerous tumors.
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Affiliation(s)
- Zeid A Nima
- Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, Little Rock, Arkansas, 72204, USA
| | - Ahmed M Alwbari
- Department of Cancer Care, Johns Hopkins Aramco Healthcare, Dhahran, 34465, Saudi Arabia.,University of Arkansas for Medical Sciences, Department of Internal Medicine, Division of Hematology/Oncology, Little Rock, Arkansas, 72205, USA
| | - Vijayalakshmi Dantuluri
- Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, Little Rock, Arkansas, 72204, USA
| | - Rabab N Hamzah
- Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, Little Rock, Arkansas, 72204, USA
| | - Natasha Sra
- Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, Little Rock, Arkansas, 72204, USA
| | - Pooja Motwani
- University of Arkansas for Medical Sciences, Department of Internal Medicine, Division of Hematology/Oncology, Little Rock, Arkansas, 72205, USA
| | - Konstantinos Arnaoutakis
- University of Arkansas for Medical Sciences, Department of Internal Medicine, Division of Hematology/Oncology, Little Rock, Arkansas, 72205, USA
| | - Rebecca A Levy
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA
| | - Amani F Bohliqa
- Maternity and Children's Hospital, Department of Pharmacy, Damam, 32253, Saudi Arabia
| | - Dmitry Nedosekin
- Arkansas Nanomedicine Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA
| | - Vladimir P Zharov
- Arkansas Nanomedicine Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA
| | - Issam Makhoul
- University of Arkansas for Medical Sciences, Department of Internal Medicine, Division of Hematology/Oncology, Little Rock, Arkansas, 72205, USA
| | - Alexandru S Biris
- Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, Little Rock, Arkansas, 72204, USA
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35
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Bansal N, Amdani S, Lipshultz ER, Lipshultz SE. Chemotherapy-induced cardiotoxicity in children. Expert Opin Drug Metab Toxicol 2017; 13:817-832. [DOI: 10.1080/17425255.2017.1351547] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Neha Bansal
- Department of Pediatrics, Wayne State University School of Medicine and Children’s Hospital of Michigan, Detroit, MI, USA
| | - Shahnawaz Amdani
- Department of Pediatrics, Wayne State University School of Medicine and Children’s Hospital of Michigan, Detroit, MI, USA
| | - Emma R. Lipshultz
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Steven E. Lipshultz
- Department of Pediatrics, Wayne State University School of Medicine and Children’s Hospital of Michigan, Detroit, MI, USA
- Karmanos Cancer Institute, Detroit, MI, USA
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36
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Srikanthan K, Klug R, Tirona M, Thompson E, Visweshwar H, Puri N, Shapiro J, Sodhi K. Creating a Biomarker Panel for Early Detection of Chemotherapy Related Cardiac Dysfunction in Breast Cancer Patients. ACTA ACUST UNITED AC 2017. [PMID: 28642833 DOI: 10.4172/2155-9880.1000507] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cardiotoxicity is an important issue for breast cancer patients receiving anthracycline-trastuzumab therapy in the adjuvant setting. Studies show that 3-36% of patients receiving anthracyclines and/or trastuzumab experience chemotherapy related cardiac dysfunction (CRCD) and approximately 17% of patients must stop chemotherapy due to the consequences of CRCD. There is currently no standardized, clinically verified way to detect CRCD early, but common practices include serial echocardiography and troponin measurements, which can be timely, costly, and not always available in areas where health care resources are scarce. Furthermore, detection of CRCD, before there is any echocardiographic evidence of dysfunction or clinical symptoms present, would allow maximal benefit of chemotherapy and minimize cardiac complications. Creating a panel of serum biomarkers would allow for more specificity and sensitivity in the early detection of CRCD, which would be easy to implement and cost effective in places with limited health care. Based on a review of the literature, we propose creating a biomarker panel consisting of topoisomerase 2β, serum troponin T/I, myeloperoxidase, NT-proBNP, miR-208b, miR-34a, and miR-150 in breast cancer patients receiving anthracyclines and/or trastuzumab to detect CRCD before any signs of overt cardiotoxicity are apparent.
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Affiliation(s)
- Krithika Srikanthan
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Rebecca Klug
- Department of Surgery, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Maria Tirona
- Division of Hematology and Oncology, Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Ellen Thompson
- Department of Cardiology, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Haresh Visweshwar
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Nitin Puri
- Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH, 43614, USA
| | - Joseph Shapiro
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Komal Sodhi
- Department of Surgery, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
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Menna P, Salvatorelli E. Primary Prevention Strategies for Anthracycline Cardiotoxicity: A Brief Overview. Chemotherapy 2017; 62:159-168. [DOI: 10.1159/000455823] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 01/07/2017] [Indexed: 11/19/2022]
Abstract
The clinical use of doxorubicin and other antitumor anthracyclines is limited by a dose-related risk of cardiomyopathy and heart failure which may occur “on treatment” or any time, from months to years, after completing chemotherapy. Dose reductions diminish the incidence of cardiac events attributable to anthracyclines, but heart failure still occurs in some patients exposed to low or moderate anthracycline doses. Because anthracyclines improve the life expectancy of patients with, for example, breast cancer or lymphomas, preventing or diminishing the risk of early or delayed cardiotoxicity is of obvious clinical importance. Here, we briefly review some potential strategies of primary prevention that are based on what we know about the molecular mechanisms of cardiotoxicity, and what can be done, or might be done, to interfere with the pharmacokinetic, pharmacodynamic, and genetic determinants of cardiotoxicity.
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de Oliveira BL, Niederer S. A Biophysical Systems Approach to Identifying the Pathways of Acute and Chronic Doxorubicin Mitochondrial Cardiotoxicity. PLoS Comput Biol 2016; 12:e1005214. [PMID: 27870850 PMCID: PMC5117565 DOI: 10.1371/journal.pcbi.1005214] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 10/20/2016] [Indexed: 11/23/2022] Open
Abstract
The clinical use of the anthracycline doxorubicin is limited by its cardiotoxicity which is associated with mitochondrial dysfunction. Redox cycling, mitochondrial DNA damage and electron transport chain inhibition have been identified as potential mechanisms of toxicity. However, the relative roles of each of these proposed mechanisms are still not fully understood. The purpose of this study is to identify which of these pathways independently or in combination are responsible for doxorubicin toxicity. A state of the art mathematical model of the mitochondria including the citric acid cycle, electron transport chain and ROS production and scavenging systems was extended by incorporating a novel representation for mitochondrial DNA damage and repair. In silico experiments were performed to quantify the contributions of each of the toxicity mechanisms to mitochondrial dysfunction during the acute and chronic stages of toxicity. Simulations predict that redox cycling has a minor role in doxorubicin cardiotoxicity. Electron transport chain inhibition is the main pathway for acute toxicity for supratherapeutic doses, being lethal at mitochondrial concentrations higher than 200μM. Direct mitochondrial DNA damage is the principal pathway of chronic cardiotoxicity for therapeutic doses, leading to a progressive and irreversible long term mitochondrial dysfunction.
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Affiliation(s)
- Bernardo L. de Oliveira
- Department of Biomedical Engineering, Division of Imaging Sciences and Biomedical Engineering, King’s College London, London, United Kingdom
| | - Steven Niederer
- Department of Biomedical Engineering, Division of Imaging Sciences and Biomedical Engineering, King’s College London, London, United Kingdom
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Menna P, Salvatorelli E, Minotti G. Rethinking Drugs from Chemistry to Therapeutic Opportunities: Pixantrone beyond Anthracyclines. Chem Res Toxicol 2016; 29:1270-8. [PMID: 27420111 DOI: 10.1021/acs.chemrestox.6b00190] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Pixantrone (6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione) has been approved by the European Medicines Agency for the treatment of refractory or relapsed non-Hodgkin's lymphoma (NHL). It is popularly referred to as a novel aza-anthracenedione, and as such it is grouped with anthracycline-like drugs. Preclinical development of pixantrone was in fact tailored to retain the same antitumor activity as that of anthracyclines or other anthracenediones while also avoiding cardiotoxicity that dose-limits clinical use of anthracycline-like drugs. Preliminary data in laboratory animals showed that pixantrone was active, primarily in hematologic malignancies, but caused significantly less cardiotoxicity than doxorubicin or mitoxantrone. Pixantrone was cardiac tolerable also in animals pretreated with doxorubicin, which anticipated a therapeutic niche for pixantrone to treat patients with a history of prior exposure to anthracyclines. This is the case for patients with refractory/relapsed NHL. Pixantrone clinical development, regulatory approval, and penetration in clinical practice were nonetheless laborious if not similar to a rocky road. Structural and nominal similarities with mitoxantrone and anthracyclines may have caused a negative influence, possibly leading to a general perception that pixantrone is a "me-too" anthracycline. Recent insights suggest this is not the case. Pixantrone shows pharmacological and toxicological mechanisms of action that are difficult to reconcile with anthracycline-like drugs. Pixantrone is a new drug with its own characteristics. For example, pixantrone causes mis-segregation of genomic material in cancer cells and inhibits formation of toxic anthracycline metabolites in cardiac cells. Understanding the differences between pixantrone and anthracyclines or mitoxantrone may help one to appreciate how it worked in the phase 3 study that led to its approval in Europe and how it might work in many more patients in everyday clinical practice, were it properly perceived as a drug with its own characteristics and therapeutic potential. The road is rocky but not a dead-end.
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Affiliation(s)
- Pierantonio Menna
- Unit of Drug Sciences, Department of Medicine, University Campus Bio-Medico , Via Alvaro del Portillo, 21, 00128 Rome, Italy
| | - Emanuela Salvatorelli
- Unit of Drug Sciences, Department of Medicine, University Campus Bio-Medico , Via Alvaro del Portillo, 21, 00128 Rome, Italy
| | - Giorgio Minotti
- Unit of Drug Sciences, Department of Medicine, University Campus Bio-Medico , Via Alvaro del Portillo, 21, 00128 Rome, Italy
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Cardiotoxicity in anthracycline therapy: Prevention strategies. REVISTA PORTUGUESA DE CARDIOLOGIA (ENGLISH EDITION) 2016. [DOI: 10.1016/j.repce.2015.12.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Cruz M, Duarte-Rodrigues J, Campelo M. Cardiotoxicity in anthracycline therapy: Prevention strategies. Rev Port Cardiol 2016; 35:359-71. [PMID: 27255173 DOI: 10.1016/j.repc.2015.12.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 12/03/2015] [Accepted: 12/20/2015] [Indexed: 11/18/2022] Open
Abstract
The increasing use of anthracyclines, together with the longer survival of cancer patients, means the toxic effects of these drugs need to be monitored. In order to detect, prevent or mitigate anthracycline-induced cardiomyopathy, it is essential that all patients undergo a rigorous initial cardiovascular assessment, followed by close monitoring. Several clinical trials have shown the cardioprotective effect of non-pharmacological measures such as exercise, healthy lifestyles, control of risk factors and treatment of comorbidities; a cardioprotective effect has also been observed with pharmacological measures such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, statins, dexrazoxane and liposomal formulations. However, there are currently no guidelines for managing prevention in these patients. In this review the authors discuss the state of the art of the assessment, monitoring, and, above all, the prevention of anthracycline-induced cardiotoxicity.
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Affiliation(s)
- Margarida Cruz
- Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | | | - Manuel Campelo
- Serviço de Cardiologia, Hospital de S. João, Porto, Portugal; Centro de Investigação em Tecnologias e Serviços de Saúde (CINTESIS), Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
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Role of nucleotide excision repair proteins in response to DNA damage induced by topoisomerase II inhibitors. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2016; 768:68-77. [PMID: 27234564 DOI: 10.1016/j.mrrev.2016.04.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 03/11/2016] [Accepted: 04/08/2016] [Indexed: 01/26/2023]
Abstract
In cancer treatment, chemotherapy is one of the main strategies used. The knowledge of the cellular and molecular characteristics of tumors allows the use of more specific drugs, making the removal of tumors more efficient. Among the drugs of choice in these treatments, topoisomerase inhibitors are widely used against different types of tumors. Topoisomerases are enzymes responsible for maintaining the structure of DNA, altering its topological state temporarily during the processes of replication and transcription, in order to avoid supercoiling and entanglements at the double helix. The DNA damage formed as a result of topoisomerase inhibition can be repaired by DNA repair mechanisms. Thus, DNA repair pathways can modulate the effectiveness of chemotherapy. Homologous recombination (HR) and non-homologous end joining (NHEJ) are the main pathways involved in the removal of double strand breaks (DSBs); while nucleotide excision repair (NER) is mainly characterized by the removal of lesions that lead to significant structural distortions in the DNA double helix. Evidence has shown that DSBs are the main type of damage resulting from the inhibition of the DNA topoisomerase II enzyme, and therefore the involvement of HR and NHEJ pathways in the repair process is well established. However, some topoisomerase II inhibitors induce other types of lesions, like DNA adducts, interstrand crosslinks and reactive oxygen species, and studies have shown that other DNA repair pathways might be participating in removing injury induced by these drugs. This review aims to correlate the involvement of proteins from different DNA repair pathways in response to these drugs, with an emphasis on NER.
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Hasinoff BB, Wu X, Patel D, Kanagasabai R, Karmahapatra S, Yalowich JC. Mechanisms of Action and Reduced Cardiotoxicity of Pixantrone; a Topoisomerase II Targeting Agent with Cellular Selectivity for the Topoisomerase IIα Isoform. J Pharmacol Exp Ther 2016; 356:397-409. [PMID: 26660439 PMCID: PMC4746493 DOI: 10.1124/jpet.115.228650] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 12/09/2015] [Indexed: 01/09/2023] Open
Abstract
Pixantrone is a new noncardiotoxic aza-anthracenedione anticancer drug structurally related to anthracyclines and anthracenediones, such as doxorubicin and mitoxantrone. Pixantrone is approved in the European Union for the treatment of relapsed or refractory aggressive B cell non-Hodgkin lymphoma. This study was undertaken to investigate both the mechanism(s) of its anticancer activity and its relative lack of cardiotoxicity. Pixantrone targeted DNA topoisomerase IIα as evidenced by its ability to inhibit kinetoplast DNA decatenation; to produce linear double-strand DNA in a pBR322 DNA cleavage assay; to produce DNA double-strand breaks in a cellular phospho-histone γH2AX assay; to form covalent topoisomerase II-DNA complexes in a cellular immunodetection of complex of enzyme-to-DNA assay; and to display cross-resistance in etoposide-resistant K562 cells. Pixantrone produced semiquinone free radicals in an enzymatic reducing system, although not in a cellular system, most likely due to low cellular uptake. Pixantrone was 10- to 12-fold less damaging to neonatal rat myocytes than doxorubicin or mitoxantrone, as measured by lactate dehydrogenase release. Three factors potentially contribute to the reduced cardiotoxicity of pixantrone. First, its lack of binding to iron(III) makes it unable to induce iron-based oxidative stress. Second, its low cellular uptake may limit its ability to produce semiquinone free radicals and redox cycle. Finally, because the β isoform of topoisomerase II predominates in postmitotic cardiomyocytes, and pixantrone is demonstrated in this study to be selective for topoisomerase IIα in stabilizing enzyme-DNA covalent complexes, the attenuated cardiotoxicity of this agent may also be due to its selectivity for targeting topoisomerase IIα over topoisomerase IIβ.
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Affiliation(s)
- Brian B Hasinoff
- College of Pharmacy, Apotex Centre, University of Manitoba, Winnipeg, Manitoba, Canada (B.B.H., X.W., D.P.); and Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio (R.K., S.K., J.C.Y.)
| | - Xing Wu
- College of Pharmacy, Apotex Centre, University of Manitoba, Winnipeg, Manitoba, Canada (B.B.H., X.W., D.P.); and Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio (R.K., S.K., J.C.Y.)
| | - Daywin Patel
- College of Pharmacy, Apotex Centre, University of Manitoba, Winnipeg, Manitoba, Canada (B.B.H., X.W., D.P.); and Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio (R.K., S.K., J.C.Y.)
| | - Ragu Kanagasabai
- College of Pharmacy, Apotex Centre, University of Manitoba, Winnipeg, Manitoba, Canada (B.B.H., X.W., D.P.); and Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio (R.K., S.K., J.C.Y.)
| | - Soumendrakrishna Karmahapatra
- College of Pharmacy, Apotex Centre, University of Manitoba, Winnipeg, Manitoba, Canada (B.B.H., X.W., D.P.); and Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio (R.K., S.K., J.C.Y.)
| | - Jack C Yalowich
- College of Pharmacy, Apotex Centre, University of Manitoba, Winnipeg, Manitoba, Canada (B.B.H., X.W., D.P.); and Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio (R.K., S.K., J.C.Y.)
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Rharass T, Gbankoto A, Canal C, Kurşunluoğlu G, Bijoux A, Panáková D, Ribou AC. Oxidative stress does not play a primary role in the toxicity induced with clinical doses of doxorubicin in myocardial H9c2 cells. Mol Cell Biochem 2016; 413:199-215. [PMID: 26833193 DOI: 10.1007/s11010-016-2653-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 01/23/2016] [Indexed: 11/26/2022]
Abstract
The implication of oxidative stress as primary mechanism inducing doxorubicin (DOX) cardiotoxicity is still questionable as many in vitro studies implied supra-clinical drug doses or unreliable methodologies for reactive oxygen species (ROS) detection. The aim of this study was to clarify whether oxidative stress is involved in compliance with the conditions of clinical use of DOX, and using reliable tools for ROS detection. We examined the cytotoxic mechanisms of 2 μM DOX 1 day after the beginning of the treatment in differentiated H9c2 rat embryonic cardiac cells. Cells were exposed for 2 or 24 h with DOX to mimic a single chronic dosage or to favor accumulation, respectively. We found that apoptosis was prevalent in cells exposed for a short period with DOX: cells showed typical hallmarks as loss of anchorage ability, mitochondrial hyperpolarization followed by the collapse of mitochondrial activity, and nuclear condensation. Increasing the exposure period favored a shift to necrosis as the cells preferentially exhibited early DNA impairment and nuclear swelling. In either case, measuring the fluorescence lifetime of 1-pyrenebutyric acid or the intensities of dihydroethidium or amplex red showed a consistent pattern in ROS production which was a slight increased level far from representative of an oxidative stress. Moreover, pre-treatment with dexrazoxane provided a cytoprotective effect although it failed to detoxify ROS. Our data support that oxidative stress is unlikely to be the primary mechanism of DOX cardiac toxicity in vitro.
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Affiliation(s)
- Tareck Rharass
- Institute of Modeling and Analysis in Geo-Environmental and Health (IMAGES_ESPACE-DEV), University of Perpignan Via Domitia, 66860, Perpignan, France
- Electrochemical Signaling in Development and Disease, Max-Delbrück-Center for Molecular Medicine (MDC), 13125, Berlin-Buch, Germany
| | - Adam Gbankoto
- Department of Animal Physiology, Faculty of Sciences and Technics, University of Abomey-Calavi, 01 BP 526, Cotonou, Benin
| | - Christophe Canal
- Institute of Modeling and Analysis in Geo-Environmental and Health (IMAGES_ESPACE-DEV), University of Perpignan Via Domitia, 66860, Perpignan, France
| | | | - Amandine Bijoux
- Institute of Modeling and Analysis in Geo-Environmental and Health (IMAGES_ESPACE-DEV), University of Perpignan Via Domitia, 66860, Perpignan, France
| | - Daniela Panáková
- Electrochemical Signaling in Development and Disease, Max-Delbrück-Center for Molecular Medicine (MDC), 13125, Berlin-Buch, Germany
| | - Anne-Cécile Ribou
- Institute of Modeling and Analysis in Geo-Environmental and Health (IMAGES_ESPACE-DEV), University of Perpignan Via Domitia, 66860, Perpignan, France.
- ESPACE-DEV, UMR UG UA UM IRD, 34093, Montpellier, France.
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Jović DS, Seke MN, Djordjevic AN, Mrđanović JŽ, Aleksić LD, Bogdanović GM, Pavić AB, Plavec J. Fullerenol nanoparticles as a new delivery system for doxorubicin. RSC Adv 2016. [DOI: 10.1039/c6ra03879d] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Fullerenol as a promising intracellular targeting carrier for the efficient delivery of antitumor drugs into tumor cells.
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Affiliation(s)
- Danica S. Jović
- Department of Chemistry
- Biochemistry and Environmental Protection
- Faculty of Sciences
- University of Novi Sad
- Novi Sad
| | - Mariana N. Seke
- Institute of Nuclear Sciences “Vinča”
- University of Belgrade
- Belgrade
- Serbia
| | - Aleksandar N. Djordjevic
- Department of Chemistry
- Biochemistry and Environmental Protection
- Faculty of Sciences
- University of Novi Sad
- Novi Sad
| | - Jasminka Ž. Mrđanović
- Oncology Institute of Vojvodina
- Faculty of Medicine
- University of Novi Sad
- Sremska Kamenica
- Serbia
| | - Lidija D. Aleksić
- Oncology Institute of Vojvodina
- Faculty of Medicine
- University of Novi Sad
- Sremska Kamenica
- Serbia
| | - Gordana M. Bogdanović
- Oncology Institute of Vojvodina
- Faculty of Medicine
- University of Novi Sad
- Sremska Kamenica
- Serbia
| | - Aleksandar B. Pavić
- Institute of Molecular Genetics and Genetic Engineering
- University of Belgrade
- Belgrade
- Serbia
| | - Janez Plavec
- Slovenian NMR Centre
- National Institute of Chemistry
- Ljubljana
- Slovenia
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Domercant J, Polin N, Jahangir E. Cardio-Oncology: A Focused Review of Anthracycline-, Human Epidermal Growth Factor Receptor 2 Inhibitor-, and Radiation-Induced Cardiotoxicity and Management. Ochsner J 2016; 16:250-256. [PMID: 27660573 PMCID: PMC5024806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023] Open
Abstract
BACKGROUND Cardio-oncology is a collaborative approach between cardiologists and oncologists in the treatment of patients with cancer and heart disease. Radiation and chemotherapy have played a major role in the decreased cancer-related mortality achieved in the past 2 decades. However, anthracycline-, tyrosine kinase-, and radiation-based therapies are each associated with independent cardiovascular (CV) risks, and these risks are cumulative when these therapies are used in combination. METHODS We analyzed several published articles, studies, and guidelines to provide a focused review of cardiotoxicity associated with anthracyclines, human epidermal growth factor receptor 2 inhibitors, and radiation therapy and its management. RESULTS The focus on CV risk among individuals being treated with cardiotoxic agents is important because once the cancer is cured, CV disease becomes the number 1 cause of death among cancer survivors. Cardio-oncology focuses on assessing CV risk prior to starting therapy, optimizing modifiable risk factors, and providing surveillance and treatment for any early signs of cardiotoxicity in patients undergoing radiation and chemotherapy. A collaborative approach between oncologists and cardiologists is integral to the optimal care of patients with cancer. Although radiation and chemotherapy treatments have evolved with the aim of targeting cancer cells while having minimal effect on the heart, the increased risk of cardiomyopathy in patients receiving these treatments remains significant. CONCLUSION Proper screening and treatment of cardiotoxicity are essential for patients with cancer. As cardiac diseases and cancer remain the first and second causes of mortality in developed nations, respectively, cardio-oncology is the answer to this group of individuals who are especially vulnerable to both causes of mortality.
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Affiliation(s)
- Jean Domercant
- Department of Internal Medicine, Leonard J. Chabert Medical Center, Houma, LA
| | - Nichole Polin
- Department of Cardiology, Ochsner Clinic Foundation, New Orleans, LA
- The University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA
| | - Eiman Jahangir
- Department of Cardiology, Ochsner Clinic Foundation, New Orleans, LA
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Rochette L, Guenancia C, Gudjoncik A, Hachet O, Zeller M, Cottin Y, Vergely C. Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms. Trends Pharmacol Sci 2015; 36:326-48. [PMID: 25895646 DOI: 10.1016/j.tips.2015.03.005] [Citation(s) in RCA: 179] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 03/16/2015] [Accepted: 03/20/2015] [Indexed: 01/26/2023]
Abstract
Anticancer drugs continue to cause significant reductions in left ventricular ejection fraction resulting in congestive heart failure. The best-known cardiotoxic agents are anthracyclines (ANTHs) such as doxorubicin (DOX). For several decades cardiotoxicity was almost exclusively associated with ANTHs, for which cumulative dose-related cardiac damage was the use-limiting step. Human epidermal growth factor (EGF) receptor 2 (HER2; ErbB2) has been identified as an important target for breast cancer. Trastuzumab (TRZ), a humanized anti-HER2 monoclonal antibody, is currently recommended as first-line treatment for patients with metastatic HER2(+) tumors. The use of TRZ may be limited by the development of drug intolerance, such as cardiac dysfunction. Cardiotoxicity has been attributed to free-iron-based, radical-induced oxidative stress. Many approaches have been promoted to minimize these serious side effects, but they are still clinically problematic. A new approach to personalized medicine for cancer that involves molecular screening for clinically relevant genomic alterations and genotype-targeted treatments is emerging.
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Affiliation(s)
- Luc Rochette
- Laboratoire de Physiopathologie et Pharmacologie Cardio-métaboliques (LPPCM), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche 866, Facultés de Médecine et de Pharmacie - Université de Bourgogne, 7 Boulevard Jeanne d'Arc, 21033 Dijon, France.
| | - Charles Guenancia
- Laboratoire de Physiopathologie et Pharmacologie Cardio-métaboliques (LPPCM), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche 866, Facultés de Médecine et de Pharmacie - Université de Bourgogne, 7 Boulevard Jeanne d'Arc, 21033 Dijon, France; Service de Cardiologie, Centre Hospitalier Universitaire Bocage, Dijon, France
| | - Aurélie Gudjoncik
- Laboratoire de Physiopathologie et Pharmacologie Cardio-métaboliques (LPPCM), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche 866, Facultés de Médecine et de Pharmacie - Université de Bourgogne, 7 Boulevard Jeanne d'Arc, 21033 Dijon, France; Service de Cardiologie, Centre Hospitalier Universitaire Bocage, Dijon, France
| | - Olivier Hachet
- Laboratoire de Physiopathologie et Pharmacologie Cardio-métaboliques (LPPCM), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche 866, Facultés de Médecine et de Pharmacie - Université de Bourgogne, 7 Boulevard Jeanne d'Arc, 21033 Dijon, France; Service de Cardiologie, Centre Hospitalier Universitaire Bocage, Dijon, France
| | - Marianne Zeller
- Laboratoire de Physiopathologie et Pharmacologie Cardio-métaboliques (LPPCM), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche 866, Facultés de Médecine et de Pharmacie - Université de Bourgogne, 7 Boulevard Jeanne d'Arc, 21033 Dijon, France
| | - Yves Cottin
- Laboratoire de Physiopathologie et Pharmacologie Cardio-métaboliques (LPPCM), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche 866, Facultés de Médecine et de Pharmacie - Université de Bourgogne, 7 Boulevard Jeanne d'Arc, 21033 Dijon, France; Service de Cardiologie, Centre Hospitalier Universitaire Bocage, Dijon, France
| | - Catherine Vergely
- Laboratoire de Physiopathologie et Pharmacologie Cardio-métaboliques (LPPCM), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche 866, Facultés de Médecine et de Pharmacie - Université de Bourgogne, 7 Boulevard Jeanne d'Arc, 21033 Dijon, France
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Deng S, Yan T, Nikolova T, Fuhrmann D, Nemecek A, Gödtel-Armbrust U, Kaina B, Wojnowski L. The catalytic topoisomerase II inhibitor dexrazoxane induces DNA breaks, ATF3 and the DNA damage response in cancer cells. Br J Pharmacol 2015; 172:2246-57. [PMID: 25521189 DOI: 10.1111/bph.13046] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 11/21/2014] [Accepted: 12/03/2014] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND AND PURPOSE The catalytic topoisomerase II inhibitor dexrazoxane has been associated not only with improved cancer patient survival but also with secondary malignancies and reduced tumour response. EXPERIMENTAL APPROACH We investigated the DNA damage response and the role of the activating transcription factor 3 (ATF3) accumulation in tumour cells exposed to dexrazoxane. KEY RESULTS Dexrazoxane exposure induced topoisomerase IIα (TOP2A)-dependent cell death, γ-H2AX accumulation and increased tail moment in neutral comet assays. Dexrazoxane induced DNA damage responses, shown by enhanced levels of γ-H2AX/53BP1 foci, ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), Chk1 and Chk2 phosphorylation, and by p53 accumulation. Dexrazoxane-induced γ-H2AX accumulation was dependent on ATM. ATF3 protein was induced by dexrazoxane in a concentration- and time-dependent manner, which was abolished in TOP2A-depleted cells and in cells pre-incubated with ATM inhibitor. Knockdown of ATF3 gene expression by siRNA triggered apoptosis in control cells and diminished the p53 protein level in both control and dexrazoxane -treated cells. This was accompanied by increased γ-H2AX accumulation. ATF3 knockdown also delayed the repair of dexrazoxane -induced DNA double-strand breaks. CONCLUSIONS AND IMPLICATIONS As with other TOP2A poisons, dexrazoxane induced DNA double-strand breaks followed by activation of the DNA damage response. The DNA damage-triggered ATF3 controlled p53 accumulation and generation of double-strand breaks and is proposed to serve as a switch between DNA damage and cell death following dexrazoxane treatment. These findings suggest a mechanistic explanation for the diverse clinical observations associated with dexrazoxane.
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Affiliation(s)
- Shiwei Deng
- Institute of Pharmacology, Medical Center of the University Mainz, Mainz, Germany
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Jirkovská-Vávrová A, Roh J, Lenčová-Popelová O, Jirkovský E, Hrušková K, Potůčková-Macková E, Jansová H, Hašková P, Martinková P, Eisner T, Kratochvíl M, Šůs J, Macháček M, Vostatková-Tichotová L, Geršl V, Kalinowski DS, Muller MT, Richardson DR, Vávrová K, Štěrba M, Šimůnek T. Synthesis and analysis of novel analogues of dexrazoxane and its open-ring hydrolysis product for protection against anthracycline cardiotoxicity in vitro and in vivo. Toxicol Res (Camb) 2015. [DOI: 10.1039/c5tx00048c] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Topoisomerase II beta, rather than (or along with) iron chelation, may be a promising target for cardioprotection.
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50
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Guo S, Wong S. Cardiovascular toxicities from systemic breast cancer therapy. Front Oncol 2014; 4:346. [PMID: 25538891 PMCID: PMC4255485 DOI: 10.3389/fonc.2014.00346] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 11/18/2014] [Indexed: 01/03/2023] Open
Abstract
Cardiovascular toxicity is unfortunately a potential short- or long-term sequela of breast cancer therapy. Both conventional chemotherapeutic agents such as anthracyclines and newer targeted agents such as trastuzumab can cause varying degrees of cardiac dysfunction. Type I cardiac toxicity is dose-dependent and irreversible, whereas Type II is not dose-dependent and is generally reversible with cessation of the drug. In this review, we discuss what is currently known about the cardiovascular effects of systemic breast cancer treatments, with a focus on the putative mechanisms of toxicity, the role of biomarkers, and potential methods of preventing and minimizing cardiovascular complications.
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Affiliation(s)
- Shuang Guo
- Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Serena Wong
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
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