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

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.

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

“…This study represents a continuation of the findings from previous research [23]. It emphasizes the complex interplay of redox balance, iron metabolism, and drug interactions in the context of anthracycline-induced cardiotoxicity.…”

“…The experiment was performed as previously described [23]. Briefly, rats were acclimatized before the study treatment began.…”

“…In this study, we investigated the role of oxidative stress in DOX-dependent late cardiomyopathy, as previously demonstrated in our earlier research on the same rats [23]. Specifically, we examined parameters associated with the redox balance, which is crucial for oxidative stress in the heart muscle (Table 3).…”

Molecular Research on Heart Protection

“…Recently, various molecular bases of heart protection have been discovered and used in many experimental and clinical investigations [ 1 , 2 , 3 ]. Protective strategies based on molecular research can positively impact a diseased heart by facilitating diagnosis and treatment of injuries and disorders [ 4 , 5 , 6 , 7 ].…”

“…Szponar et al (2023) generated a model of chronic anthracycline-induced cardiomyopathy [ 1 ]. They conducted functional, morphological, biochemical, and molecular studies to examine if combining DEX and CVD pretreatments can attenuate ANT-induced cardiomyopathy.…”