The long-term clinical usefulness of doxorubicin (DOX), an anthracycline with potent antitumor activity, is limited by DOX-induced cardiotoxicity. Kaempferol, one of the most common dietary flavonoids, is known to have anti-apoptotic, anti-oxidative, and anti-inflammatory properties. The current study aimed to investigate the possible protective effect of kaempferol against DOX-induced cardiotoxicity and the underlying mechanisms. Rats were intraperitoneally (i.p.) treated with DOX (3 mg/kg) every other day for a cumulative dose of 9 mg/kg. After 28 days, DOX caused retarded body and heart growth, oxidative stress, apoptotic damage, mitochondrial dysfunction, and Bcl-2 expression disturbance. In contrast, kaempferol pretreatment (10 mg/kg i.p. before DOX administration) attenuated the DOX-induced apoptotic damage in heart tissues. In vitro studies also indicated that kaempferol may have used the mitochondrion-dependent pathway to counteract the DOX-induced cardiotoxicity. This counteraction was achieved by inhibiting p53 expression and its binding to the promoter region of the Bax proapoptotic gene, but not to the Bcl-2 antiapoptotic gene. Kaempferol also effectively suppressed DOX-induced extracellular signal-regulated kinase (ERK) 1/2 activation, but had no effect on p38 and JNK. Therefore, kaempferol protected against DOX-induced cardiotoxicity, at least, partially, by inhibiting the activation of p53-mediated, mitochondrion-dependent apoptotic signaling, and by being involved in an ERK-dependent mitogen-activated protein kinase pathway. These findings elucidated the potential of kaempferol as a promising reagent for treating DOX-induced cardiotoxicity, and may have implications in the long-term clinical usefulness of DOX.
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