{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T23:51:38Z","timestamp":1781221898383,"version":"3.54.1"},"reference-count":36,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T00:00:00Z","timestamp":1707782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical University of Lublin","award":["DS380"],"award-info":[{"award-number":["DS380"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Late cardiotoxicity is a formidable challenge in anthracycline-based anticancer treatments. Previous research hypothesized that co-administration of carvedilol (CVD) and dexrazoxane (DEX) might provide superior protection against doxorubicin (DOX)-induced cardiotoxicity compared to DEX alone. However, the anticipated benefits were not substantiated by the findings. This study focuses on investigating the impact of CVD on myocardial redox system parameters in rats treated with DOX + DEX, examining its influence on overall toxicity and iron metabolism. Additionally, considering the previously observed DOX-induced ascites, a seldom-discussed condition, the study explores the potential involvement of the liver in ascites development. Compounds were administered weekly for ten weeks, with a specific emphasis on comparing parameter changes between DOX + DEX + CVD and DOX + DEX groups. Evaluation included alterations in body weight, feed and water consumption, and analysis of NADPH2, NADP+, NADPH2\/NADP+, lipid peroxidation, oxidized DNA, and mRNA for superoxide dismutase 2 and catalase expressions in cardiac muscle. The iron management panel included markers for iron, transferrin, and ferritin. Liver abnormalities were assessed through histological examinations, aspartate transaminase, alanine transaminase, and serum albumin level measurements. During weeks 11 and 21, reduced NADPH2 levels were observed in almost all examined groups. Co-administration of DEX and CVD negatively affected transferrin levels in DOX-treated rats but did not influence body weight changes. Ascites predominantly resulted from cardiac muscle dysfunction rather than liver-related effects. The study\u2019s findings, exploring the impact of DEX and CVD on DOX-induced cardiotoxicity, indicate a lack of scientific justification for advocating the combined use of these drugs at histological, biochemical, and molecular levels.<\/jats:p>","DOI":"10.3390\/ijms25042219","type":"journal-article","created":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T04:09:21Z","timestamp":1707797361000},"page":"2219","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Assessment of the Impact of Carvedilol Administered Together with Dexrazoxan and Doxorubicin on Liver Structure and Function, Iron Metabolism, and Myocardial Redox System in Rats"],"prefix":"10.3390","volume":"25","author":[{"given":"Jaroslaw","family":"Szponar","sequence":"first","affiliation":[{"name":"Toxicology Clinic, Faculty of Medicine, Medical University of Lublin, 100 Krasnik Avenue, 20-550 Lublin, Poland"},{"name":"Clinical Department of Toxicology and Cardiology, Stefan Wyszynski Regional Specialist Hospital, 100 Krasnik Avenue, 20-550 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Gorska","sequence":"additional","affiliation":[{"name":"Toxicology Clinic, Faculty of Medicine, Medical University of Lublin, 100 Krasnik Avenue, 20-550 Lublin, Poland"},{"name":"Clinical Department of Toxicology and Cardiology, Stefan Wyszynski Regional Specialist Hospital, 100 Krasnik Avenue, 20-550 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3375-3821","authenticated-orcid":false,"given":"Marta","family":"Ostrowska-Lesko","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Medical University of Lublin, 8b Jaczewski Street, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2027-9681","authenticated-orcid":false,"given":"Agnieszka","family":"Korga-Plewko","sequence":"additional","affiliation":[{"name":"Independent Medical Biology Unit, Medical University, 8b Jaczewski Street, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Tchorz","sequence":"additional","affiliation":[{"name":"Toxicology Clinic, Faculty of Medicine, Medical University of Lublin, 100 Krasnik Avenue, 20-550 Lublin, Poland"},{"name":"Clinical Department of Toxicology and Cardiology, Stefan Wyszynski Regional Specialist Hospital, 100 Krasnik Avenue, 20-550 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0058-896X","authenticated-orcid":false,"given":"Erwin","family":"Ciechanski","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Medical University of Lublin, 8b Jaczewski Street, 20-090 Lublin, Poland"},{"name":"Clinical Department of Cardiology, Stefan Wyszynski Regional Specialist Hospital, 100 Krasnik Avenue, 20-550 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7905-2871","authenticated-orcid":false,"given":"Anna","family":"Dabrowska","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Medical University of Lublin, 8b Jaczewski Street, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4359-3953","authenticated-orcid":false,"given":"Ewa","family":"Poleszak","sequence":"additional","affiliation":[{"name":"Department of Applied Pharmacy, Medical University of Lublin, 1 Chod\u017ako Street, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franciszek","family":"Burdan","sequence":"additional","affiliation":[{"name":"Human Anatomy Department, Medical University of Lublin, 4 Jaczewski Street, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslaw","family":"Dudka","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Medical University of Lublin, 8b Jaczewski Street, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2903-4912","authenticated-orcid":false,"given":"Marek","family":"Murias","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Poznan University of Medical Sciences, 3 Rokietnicka Street, 60-608 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Slawomir","family":"Mandziuk","sequence":"additional","affiliation":[{"name":"Department of Pneumology, Oncology and Allergology, Medical University of Lublin, 8 Jaczewski Street, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kalyanaraman, B. (2020). Teaching the Basics of the Mechanism of Doxorubicin-Induced Cardiotoxicity: Have We Been Barking up the Wrong Tree?. Redox Biol., 29.","DOI":"10.1016\/j.redox.2019.101394"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"119527","DOI":"10.1016\/j.lfs.2021.119527","article-title":"A Comprehensive Review on Time-Tested Anticancer Drug Doxorubicin","volume":"278","author":"Sritharan","year":"2021","journal-title":"Life Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/B978-0-12-411638-2.00002-1","article-title":"Chapter Two\u2014The Intricate Role of CXCR4 in Cancer","volume":"Volume 124","author":"Pomper","year":"2014","journal-title":"Advances in Cancer Research"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1124\/pr.56.2.6","article-title":"Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity","volume":"56","author":"Minotti","year":"2004","journal-title":"Pharmacol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e005910","DOI":"10.1161\/CIRCHEARTFAILURE.119.005910","article-title":"Anthracycline Cardiotoxicity","volume":"12","author":"Narezkina","year":"2019","journal-title":"Circ. Heart Fail."},{"key":"ref_6","unstructured":"Ajaykumar, C. (2020). Advances in Precision Medicine Oncology, IntechOpen."},{"key":"ref_7","unstructured":"Doxorubicin (2012). LiverTox: Clinical and Research Information on Drug-Induced Liver Injury."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1093\/toxres\/tfad072","article-title":"Clinical Observation of Liposomal Doxorubicin on Liver and Renal Function in Patients with Breast Cancer","volume":"12","author":"Li","year":"2023","journal-title":"Toxicol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"363","DOI":"10.2217\/FCA.15.35","article-title":"Managing Anthracycline-Induced Cardiotoxicity: Beginning with the End in Mind","volume":"11","author":"Salvatorelli","year":"2015","journal-title":"Future Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/j.jacc.2014.06.1167","article-title":"Prevention of Anthracycline-Induced Cardiotoxicity: Challenges and Opportunities","volume":"64","author":"Vejpongsa","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Chen, Y., Shi, S., and Dai, Y. (2022). Research Progress of Therapeutic Drugs for Doxorubicin-Induced Cardiomyopathy. Biomed. Pharmacother. Biomedecine Pharmacother., 156.","DOI":"10.1016\/j.biopha.2022.113903"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2663","DOI":"10.2217\/fon-2018-0210","article-title":"Risk-Benefit of Dexrazoxane for Preventing Anthracycline-Related Cardiotoxicity: Re-Evaluating the European Labeling","volume":"14","author":"Reichardt","year":"2018","journal-title":"Future Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/S1734-1140(09)70018-0","article-title":"Anthracycline-Induced Cardiotoxicity: Overview of Studies Examining the Roles of Oxidative Stress and Free Cellular Iron","volume":"61","author":"Hrdina","year":"2009","journal-title":"Pharmacol. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fiuza, M. (2012). Cardiotoxicity of Oncologic Treatments, InTech.","DOI":"10.5772\/2170"},{"key":"ref_15","first-page":"e008209","article-title":"Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation","volume":"14","author":"Karabanovich","year":"2021","journal-title":"Circ. Heart Fail."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1038\/nm.2919","article-title":"Identification of the Molecular Basis of Doxorubicin-Induced Cardiotoxicity","volume":"18","author":"Zhang","year":"2012","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40959-019-0036-7","article-title":"Upfront Dexrazoxane for the Reduction of Anthracycline-Induced Cardiotoxicity in Adults with Preexisting Cardiomyopathy and Cancer: A Consecutive Case Series","volume":"5","author":"Ganatra","year":"2019","journal-title":"Cardio Oncol."},{"key":"ref_18","unstructured":"Eneh, C., and Lekkala, M.R. (2024). StatPearls, StatPearls Publishing."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1097\/FJC.0000000000000470","article-title":"Cardioprotective Effects of Carvedilol in Inhibiting Doxorubicin-Induced Cardiotoxicity","volume":"69","author":"Nabati","year":"2017","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1159\/000442722","article-title":"Carvedilol Administration Can Prevent Doxorubicin-Induced Cardiotoxicity: A Double-Blind Randomized Trial","volume":"134","author":"Hosseini","year":"2016","journal-title":"Cardiology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1016\/j.jacc.2018.02.049","article-title":"Carvedilol for Prevention of Chemotherapy-Related Cardiotoxicity","volume":"71","author":"Avila","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Be\u021biu, A.M., Noveanu, L., H\u00e2ncu, I.M., Lascu, A., Petrescu, L., Maack, C., Elm\u00e9r, E., and Muntean, D.M. (2022). Mitochondrial Effects of Common Cardiovascular Medications: The Good, the Bad and the Mixed. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232113653"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Szponar, J., Ciechanski, E., Ostrowska-Lesko, M., Gorska, A., Tchorz, M., Dabrowska, A., Dudka, J., Murias, M., Kowalczyk, M., and Korga-Plewko, A. (2023). The Lack of Synergy between Carvedilol and the Preventive Effect of Dexrazoxane in the Model of Chronic Anthracycline-Induced Cardiomyopathy. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241210202"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Finn, N.A., Findley, H.W., and Kemp, M.L. (2011). A Switching Mechanism in Doxorubicin Bioactivation Can Be Exploited to Control Doxorubicin Toxicity. PLoS Comput. Biol., 7.","DOI":"10.1371\/journal.pcbi.1002151"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Barata, I.S., Gomes, B.C., Rodrigues, A.S., Rueff, J., Kranendonk, M., and Esteves, F. (2022). The Complex Dynamic of Phase I Drug Metabolism in the Early Stages of Doxorubicin Resistance in Breast Cancer Cells. Genes, 13.","DOI":"10.3390\/genes13111977"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.freeradbiomed.2006.11.013","article-title":"Gp91phox-Containing NAD(P)H Oxidase Increases Superoxide Formation by Doxorubicin and NADPH","volume":"42","author":"Deng","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9287","DOI":"10.1158\/0008-5472.CAN-10-2664","article-title":"Nox2 NADPH Oxidase Promotes Pathologic Cardiac Remodeling Associated with Doxorubicin Chemotherapy","volume":"70","author":"Zhao","year":"2010","journal-title":"Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1620\/tjem.207.249","article-title":"The Protective Effects of Amifostine on Adriamycin-Induced Acute Cardiotoxicity in Rats","volume":"207","author":"Bolaman","year":"2005","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1002\/jat.945","article-title":"Protective Effects of Caffeic Acid Phenethyl Ester on Doxorubicin-Induced Cardiotoxicity in Rats","volume":"24","author":"Fadillioglu","year":"2004","journal-title":"J. Appl. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1023\/A:1014862912783","article-title":"Early Changes in Myocardial Antioxidant Enzymes in Rats Treated with Adriamycin","volume":"232","author":"Li","year":"2002","journal-title":"Mol. Cell. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e132747","DOI":"10.1172\/jci.insight.132747","article-title":"Mitochondria-Dependent Ferroptosis Plays a Pivotal Role in Doxorubicin Cardiotoxicity","volume":"5","author":"Tadokoro","year":"2020","journal-title":"JCI Insight"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Dozic, S., Howden, E.J., Bell, J.R., Mellor, K.M., Delbridge, L.M.D., and Weeks, K.L. (2023). Cellular Mechanisms Mediating Exercise-Induced Protection against Cardiotoxic Anthracycline Cancer Therapy. Cells, 12.","DOI":"10.3390\/cells12091312"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wu, B.B., Leung, K.T., and Poon, E.N.-Y. (2022). Mitochondrial-Targeted Therapy for Doxorubicin-Induced Cardiotoxicity. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031912"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1111\/apha.12162","article-title":"Blockade of Mitochondrial Calcium Uniporter Prevents Cardiac Mitochondrial Dysfunction Caused by Iron Overload","volume":"210","author":"Sripetchwandee","year":"2014","journal-title":"Acta Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e13324","DOI":"10.1111\/apha.13324","article-title":"Keeping Heart Homeostasis in Check through the Balance of Iron Metabolism","volume":"228","author":"Vela","year":"2020","journal-title":"Acta Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1097\/CRD.0b013e3182a67805","article-title":"Cardiac Involvement in Hemochromatosis","volume":"22","author":"Gulati","year":"2014","journal-title":"Cardiol. Rev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/4\/2219\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:59:05Z","timestamp":1760104745000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/4\/2219"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,13]]},"references-count":36,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["ijms25042219"],"URL":"https:\/\/doi.org\/10.3390\/ijms25042219","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,13]]}}}