title: Kaempferol protects against doxorubicin-induced cardiotoxicity in vivo and in vitro.
abstract: 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.
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.forename: Gui-Bo
authors.initials: GB
authors.lastname: Sun
authors.forename: Bing
authors.initials: B
authors.lastname: Sun
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Ling
authors.initials: L
authors.lastname: He
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Rong-Chang
authors.initials: RC
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Ren
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Sun
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology*; D054715:Cardiotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D044949:Kaempferols / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002316:Cardiotonic Agents; D054715:Cardiotoxins; D044949:Kaempferols; C006552:kaempferol; D004317:Doxorubicin