The Role of Flavonoids as a Cardioprotective Strategy against Doxorubicin-Induced Cardiotoxicity: A Review

Doxorubicin is a widely used and promising anticancer drug; however, a severe dose-dependent cardiotoxicity hampers its therapeutic value. Doxorubicin may cause acute and chronic issues, depending on the duration of toxicity. In clinical practice, the accumulative toxic dose is up to 400 mg/m(2) and increasing the dose will increase the probability of cardiac toxicity. Several molecular mechanisms underlying the pathogenesis of doxorubicin cardiotoxicity have been proposed, including oxidative stress, topoisomerase beta II inhibition, mitochondrial dysfunction, Ca(2+) homeostasis dysregulation, intracellular iron accumulation, ensuing cell death (apoptosis and necrosis), autophagy, and myofibrillar disarray and loss. Natural products including flavonoids have been widely studied both in cell, animal, and human models which proves that flavonoids alleviate cardiac toxicity caused by doxorubicin. This review comprehensively summarizes cardioprotective activity flavonoids including quercetin, luteolin, rutin, apigenin, naringenin, and hesperidin against doxorubicin, both in in vitro and in vivo models.