The Lack of Synergy between Carvedilol and the Preventive Effect of Dexrazoxane in the Model of Chronic Anthracycline-Induced Cardiomyopathy

Author:

Szponar Jaroslaw12ORCID,Ciechanski Erwin34,Ostrowska-Lesko Marta4ORCID,Gorska Agnieszka12,Tchorz Michal12,Dabrowska Anna4,Dudka Jaroslaw4,Murias Marek5ORCID,Kowalczyk Michał6ORCID,Korga-Plewko Agnieszka7ORCID,Mandziuk Slawomir8

Affiliation:

1. Toxicology Clinic, Faculty of Medicine, Medical University of Lublin, 100 Krasnik Avenue, 20-550 Lublin, Poland

2. Clinical Department of Toxicology and Cardiology, Regional Specialist Hospital, 100 Krasnik Avenue, 20-550 Lublin, Poland

3. Clinical Department of Cardiology, Regional Specialist Hospital, 100 Krasnik Avenue, 20-550 Lublin, Poland

4. Chair and Department of Toxicology, Medical University of Lublin, 8b Jaczewski Street, 20-090 Lublin, Poland

5. Chair and Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd Street, 60-572 Poznan, Poland

6. First Department of Anaesthesiology and Intensive Care, Medical University of Lublin, ul. Jaczewskiego 8, 20-954 Lublin, Poland

7. Independent Medical Biology Unit, Medical University of Lublin, 8b Jaczewski Street, 20-090 Lublin, Poland

8. Department of Pneumology, Oncology and Allergology, Medical University of Lublin, 8 Jaczewski Street, 20-090 Lublin, Poland

Abstract

The anticancer efficacy of doxorubicin (DOX) is dose-limited because of cardiomyopathy, the most significant adverse effect. Initially, cardiotoxicity develops clinically silently, but it eventually appears as dilated cardiomyopathy with a very poor prognosis. Dexrazoxane (DEX) is the only FDA-approved drug to prevent the development of anthracycline cardiomyopathy, but its efficacy is insufficient. Carvedilol (CVD) is another product being tested in clinical trials for the same indication. This study’s objective was to evaluate anthracycline cardiotoxicity in rats treated with CVD in combination with DEX. The studies were conducted using male Wistar rats receiving DOX (1.6 mg/kg b.w. i.p., cumulative dose: 16 mg/kg b.w.), DOX and DEX (25 mg/kg b.w. i.p.), DOX and CVD (1 mg/kg b.w. i.p.), or a combination (DOX + DEX + CVD) for 10 weeks. Afterward, in the 11th and 21st weeks of the study, echocardiography (ECHO) was performed, and the tissues were collected. The addition of CVD to DEX as a cardioprotective factor against DOX had no favorable advantages in terms of functional (ECHO), morphological (microscopic evaluation), and biochemical alterations (cardiac troponin I and brain natriuretic peptide levels), as well as systemic toxicity (mortality and presence of ascites). Moreover, alterations caused by DOX were abolished at the tissue level by DEX; however, when CVD was added, the persistence of DOX-induced unfavorable alterations was observed. The addition of CVD normalized the aberrant expression of the vast majority of indicated genes in the DOX + DEX group. Overall, the results indicate that there is no justification to use a simultaneous treatment of DEX and CVD in DOX-induced cardiotoxicity.

Funder

Medical University of Lublin

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference35 articles.

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