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Adriamycin is a well-known anthracycline chemotherapeutic agent widely used in treating a variety of malignancies. However, Adriamycin's clinical use is limited due to its adverse side-effects, most importantly cardiomyopathy. Adriamycin-induced cardiotoxicity reportedly includes mitochondrial dysfunction. We hypothesize that modulation of KLF4, a key regulator of cardiac mitochondrial homeostasis might play a role in the development of Adriamycin-induced cardiomyopathy. Therefore, in the current work, we evaluated the interaction of Adriamycin with KLF4 and its subsequent downstream targets. Molecular docking revealed that Adriamycin interacts strongly with KLF4 at residues Thr 448, Arg 452, Ser 444 falls within C2H2 motif which is the active site. Quantitative real-time PCR also revealed that KLF4 is downregulated by Adriamycin in cardiomyocytes in vitro. The expression of KLF4 is downregulated in a dose-dependent manner, with a 0.12 ± 0.09-fold (p ≤ 0.05, n = 3) downregulation at a low dosage and 0.21 ± 0.02-fold (p ≤ 0.05, n = 3) downregulation at high dosage. Deficiency of KLF4 leads to an impairment of PPARγ that consequently supresses the proteins/enzymes involved in the fatty acid metabolism. Adriamycin-mediated suppression of KLF4 also affected the expression of PPARα in vitro. PPARα dysfunction is likely to cause defects in β-oxidation which ultimately results in impaired ATP synthesis. Cardiac cells are thus forced to switch over the substrate from free fatty acid to glucose. Moreover, Adriamycin elevates the expression of PPARβ due to downregulation of KLF4 leads to increased myocardial glucose utilization. Thus, a change in substrate preference affects the flexibility of metabolic network culminating in diminished energy production and other regulatory activities, altogether contributing to the development of cardiomyopathy. Thus, we conclude that the effect of Adriamycin on KLF4 disrupts mitochondrial homeostasis and lipid/glucose homeostasis resulting in a reduction of ATP synthesis which ultimately results in dilated cardiomyopathy. [ABSTRACT FROM AUTHOR]

Adriamycin is an effective anti‐neoplastic drug against a variety of cancer types. However, the drug causes adverse side effects in a number of organ systems. Cardiomyopathy is one of the life‐threatening side effects of Adriamycin. In the current work, we have derived a hypothesis with possible involvement of PPAR family members in the development of Adriamycin‐induced cardiomyopathy. Dysregulation of PPAR family by Adriamycin causes impairment in the transport and β‐oxidation of fatty acids, the key substrate for ATP synthesis in heart. Evidences suggest that dysregulation of PPAR family alters the recruitment of glucose transporters. Furthermore, heme oxygenase‐1 is a crucial enzyme regulating the iron homeostasis in the heart whose expression is regulated by PPAR family. Inverse relationship exists between the expression levels of PPARγ and heme oxygenase‐1. Adriamycin upregulates the expression of heme oxygenase‐1 which in turn disrupts the iron homeostasis in cardiomyocytes. Our molecular docking results show that Adriamycin has a high affinity for iron‐binding sites of heme oxygenase‐1, thereby hindering formation of iron–sulfur complex. The lack of iron–sulfur complex impairs the electron transport chain. In addition, succinate dehydrogenase subunit A is downregulated by Adriamycin. The lack of this subunit uncouples Krebs cycle from ETC. Further, lack of this subunit increases the concentration of succinate, which further alters the mitochondrial membrane potential. Overall, in the present work, we hypothesize that alteration in the expression of PPAR family members is one of the major causes of metabolic chaos and oxidative stress caused by Adriamycin during the development of cardiomyopathy. Adriamycin, though an effective antineoplastic drug, its clinical application is hindered because of side effects, especially the irreversible dilated cardiomyopathy. The current work hypothesizes the role of PPAR family members in Adriamycin‐induced cardiomyopathy. Dysregulation of PPARs by Adriamycin impairs glucose transport and β‐oxidation. Molecular docking show that Adriamycin has high affinity for iron binding sites of hemeoxygenase‐1, thereby hindering formation of iron‐sulfur complex. Lack of iron‐sulfur complex impairs the electron transport chain thereby impairing ATP synthesis. [ABSTRACT FROM AUTHOR]