title: Roles of oxidative stress and Akt signaling in doxorubicin cardiotoxicity.
abstract: Cardiotoxicity is a treatment-limiting side effect of the anticancer drug doxorubicin (DOX). We have now investigated the roles of oxidative stress and signaling by the protein kinase Akt in DOX-induced cardiotoxicity as well as the effects on such toxicity both of fenofibrate, an agonist of peroxisome proliferator-activated receptor-alpha, and of polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), an antioxidant. Mice injected intraperitoneally with DOX were treated for 4 days with fenofibrate or PEG-SOD. Fenofibrate and PEG-SOD each prevented the induction of cardiac dysfunction by DOX. Both drugs also inhibited the activation of the transcription factor NF-kappaB and increase in lipid peroxidation in the left ventricle induced by DOX, whereas only PEG-SOD inhibited the DOX-induced activation of Akt and Akt-regulated gene expression. These results suggest that fenofibrate and PEG-SOD prevented cardiac dysfunction induced by DOX through normalization of oxidative stress and redox-regulated NF-kappaB signaling.
authors.affiliation: Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Mie 514-8507, Japan. saho@gene.mie-u.ac.jp
authors.forename: Sahoko
authors.initials: S
authors.lastname: Ichihara
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Yamada
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Kawai
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Osawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Furuhashi
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Duan
authors.forename: Gaku
authors.initials: G
authors.lastname: Ichihara
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage*; D004338:Drug Combinations; D011345:Fenofibrate / Q000008:administration & dosage*; D000960:Hypolipidemic Agents / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000503:physiopathology* / Q000517:prevention & control
chemical_list: D004338:Drug Combinations; D000960:Hypolipidemic Agents; D004317:Doxorubicin; D051058:Oncogene Protein v-akt; D011345:Fenofibrate