The Effects of Polyphenols on Doxorubicin‐Induced Nephrotoxicity by Modulating Inflammatory Cytokines, Apoptosis, Oxidative Stress, and Oxidative DNA Damage

ABSTRACT Doxorubicin (DOX) is an anthracyclic antibiotic with anti‐neoplastic activity that has been found to be a highly effective and commonly used chemotherapeutic agent in the treatment of a variety of solid and hematologic malignancies. However, its effectiveness has been limited by the occurrence of dose‐related renal, myocardial, and bone marrow toxicities. The clinical use of DOX is associated with nephrotic syndrome characterized by heavy proteinuria, hypoalbuminemia, and hyperlipidemia. DOX‐induced changes in the renal tissue of rats include increased glomerular capillary permeability and tubular atrophy. Several lines of evidence suggest that reactive oxygen species and oxidative stress have been associated with DOX‐induced renal damage. The mechanism of DOX‐induced nephrotoxicity is believed to be mediated through free radical formation, iron‐dependent oxidative damage of biological macromolecules, and membrane lipid peroxidation. Polyphenols are present in high concentration in fruits and vegetables. They have been shown to have potent antioxidant and cytoprotective effects in preventing endothelial apoptosis caused by oxidants. Treatment with polyphenols has been shown to prevent liver damage and suppress overexpression of inducible nitric oxide synthase, which is induced by various inflammatory stimuli. In addition, epidemiological studies have suggested that the intake of polyphenols may be associated with a reduced risk of DOX‐induced nephrotoxicity by modulating inflammatory cytokines, apoptosis, oxidative stress, and oxidative DNA damage. Therefore, in the present review, we examined the influence of polyphenols on DOX‐induced nephrotoxicity.