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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., (© 2022 John Wiley & Sons Ltd.)

The anticancer drug doxorubicin has been associated with several adverse side-effects including reproductive toxicity in both genders. The current review has complied the mechanisms of doxorubicin induced reproductive toxicity. The articles cited in the review were searched using Google Scholar, PubMed, Scopus, Science Direct. Doxorubicin treatment has been found to cause a decrease in testicular mass along with histopathological deformities, oligospermia and abnormalities in sperm morphology. Apart from severely affecting the normal physiological role of both Leydig cells and Sertoli cells, doxorubicin also causes chromosome abnormalities and affects DNA methylase enzyme. Testicular lipid metabolism has been found to be negatively affected by doxorubicin treatment resulting in altered profile of sphingolipids glycerophospholipids and neutral lipids. Dysregulation of 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β- hydroxysteroid dehydrogenase (17β-HSD) are strongly linked to testicular exposure to doxorubicin. Further, oxidative stress along with endoplasmic reticulum stress are also found to aggravate the male reproductive functioning in doxorubicin treated conditions. Several antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase (GPx) are downregulated by doxorubicin. It also disturbs the hormones of the hypothalamic-pituitary-gonadal (HPG)-axis including testosterone, luteinizing hormone, follicle stimulating hormone etc. In females, the drug disturbs folliculogenesis and oogenesis leading to failure of ovulation and uterine cycle. In rodent model the drug shortens pro-estrous and estrous phases. It was also found that doxorubicin causes mitochondrial dysfunction in oocytes with impaired calcium signaling along with ER stress. The goal of the present review is to comprehends various pathways due to which doxorubicin treatment promotes toxicity in male and female reproductive system., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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 a widely used drug for the treatment of various types of cancers, but its clinical application is limited because of irreversible dilated cardiomyopathy. The incidence of cardiomyopathy is a consequence of disrupted energy production, which could be related to the defects in glycogen, lipid and mucopolysaccharide metabolism. We explored the effect of Adriamycin on enzymes involved in glycolysis and apoptotic genes through molecular docking. We used Saccharomyces cerevisiae as model organism and studied the effect of Adriamycin on selected enzymes involved in glycolysis. The docking studies revealed that Adriamycin interacts with phosphofructokinase and enolase in an efficient manner. In phosphofructokinase, Adriamycin binds at the active site and with enolase the drug interacts at the cofactor-binding site (Mg2+) which might impair the activity of the enzyme. Gene expression studies revealed that Adriamycin causes the dysregulation of glycolysis through dysregulation of hexokinase, phosphoglycerate mutase, enolase and downregulation of pyruvate kinase. The drug shows a biphasic effect on the expression of genes enolase and pyruvate kinase. The impairment in glycolysis might reduce the ATP synthesis, and the cells might be deprived of energy. The condition is further worsened by elevated ROS levels triggering the cell to undergo apoptosis evidenced by downregulation of SOD and upregulation of BAX and caspase. In conclusion, our study reveals that Adriamycin impairs glycolysis and cause cell to undergo apoptosis due to oxidative stress in yeast cells. [ABSTRACT FROM AUTHOR]