Integrating Metabolomics, Histopathology, and Cardiac Marker Analysis to Assess Valsartan's Efficacy in Mitigating Dasatinib-Induced Cardiac Toxicity in Sprague-Dawley Rats

• Published in: Drug design, development and therapy development and therapy, 2024, Vol.18, p.5641-5654
• Main Authors: Alhazzani, Khalid, Mohammed, Hanan, Algahtani, Mohammad M, Aljerian, Khaldoon, Alhoshani, Ali, As Sobeai, Homood M, Ahamad, Syed Rizwan, Alotaibi, Moureq R, Alhamed, Abdullah S, Alasmari, Fawaz, Alqinyah, Mohammed, Alhamami, Hussain N, Alanazi, Ahmed Z
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Bcl-2 protein; Biomarkers; Biomarkers - metabolism; Body weight; Body weight loss; Cancer therapies; cardiac toxicity; Cardiotoxicity; Caspase-3; dasatinib; Dasatinib - administration & dosage; Dasatinib - pharmacology; Drug dosages; Effectiveness; Ethics; Evaluation; Heart; Heart rate; Histopathology; Injury analysis; Ketamine; Kinases; Leukemia; Male; Medical laboratories; Metabolism; Metabolites; Metabolomics; Monoclonal antibodies; Mortality; Myocardium - metabolism; Myocardium - pathology; Original Research; Proteins; Rats; Rats, Sprague-Dawley; Rats, Wistar; Serum levels; Survival; Toxicity; valsartan; Valsartan - pharmacology; Weight loss; Young adults
• ISSN: 1177-8881
• DOI: 10.2147/DDDT.S497212

Dasatinib (DASA) is associated with cardiotoxic effects, posing risks to patients. Valsartan (VAL) may offer protective benefits against these effects. This study evaluates the impact of DASA, VAL, and their combination on cardiac health. Wistar rats were treated with DASA, VAL, and a combination of VAL and DASA intraperitoneally every other day for 14 days. Body weight and survival rates were monitored. Serum levels of cardiac biomarkers (CPK, LDH, AST) were analyzed. Histopathological and immunohistochemical analyses assessed myocardial architecture and apoptosis-related protein expression. Metabolomic profiling was conducted using GC-MS to identify metabolic changes across treatment groups. The DASA group experienced significant weight loss and a 50% mortality rate, while the combination group had no mortality. Cardiac biomarkers like CPK, LDH, and AST were elevated in the DASA group but significantly reduced in the VAL + DASA group. Histopathological examination showed significant myocardial injury in the DASA group, with improved cardiac tissue morphology in the combination group. Immunohistochemical analysis revealed altered expression of apoptosis-related proteins, including caspase-3 and BCL-2, with improved levels in the combination group compared to DASA alone. Metabolomic profiling identified significant metabolic shifts, with 15 metabolites differentiating the treatment groups, and the VAL + DASA group mitigated the metabolic disturbances caused by DASA. The study suggesting VAL's potential therapeutic role in managing DASA-induced cardiac toxicity. The combination of VAL with DASA not only improved survival rates and reduced cardiac biomarker levels but also preserved myocardial architecture and normalized metabolic profiles. These findings highlight the importance of integrated approaches in evaluating drug efficacy and suggest VAL as a promising candidate for protecting cardiac function in preclinical models of DASA therapy.