title: Early transcriptional changes in cardiac mitochondria during chronic doxorubicin exposure and mitigation by dexrazoxane in mice.
abstract: Identification of early biomarkers of cardiotoxicity could help initiate means to ameliorate the cardiotoxic actions of clinically useful drugs such as doxorubicin (DOX). Since DOX has been shown to target mitochondria, transcriptional levels of mitochondria-related genes were evaluated to identify early candidate biomarkers in hearts of male B6C3F1 mice given a weekly intravenous dose of 3mg/kg DOX or saline (SAL) for 2, 3, 4, 6, or 8 weeks (6, 9, 12, 18, or 24 mg/kg cumulative DOX doses, respectively). Also, a group of mice was pretreated (intraperitoneally) with the cardio-protectant, dexrazoxane (DXZ; 60 mg/kg) 30 min before each weekly dose of DOX or SAL. At necropsy a week after the last dose, increased plasma concentrations of cardiac troponin T (cTnT) were detected at 18 and 24 mg/kg cumulative DOX doses, whereas myocardial alterations were observed only at the 24 mg/kg dose. Of 1019 genes interrogated, 185, 109, 140, 184, and 451 genes were differentially expressed at 6, 9, 12, 18, and 24 mg/kg cumulative DOX doses, respectively, compared to concurrent SAL-treated controls. Of these, expression of 61 genes associated with energy metabolism and apoptosis was significantly altered before and after occurrence of myocardial injury, suggesting these as early genomics markers of cardiotoxicity. Much of these DOX-induced transcriptional changes were attenuated by pretreatment of mice with DXZ. Also, DXZ treatment significantly reduced plasma cTnT concentration and completely ameliorated cardiac alterations induced by 24 mg/kg cumulative DOX. This information on early transcriptional changes during DOX treatment may be useful in designing cardioprotective strategies targeting mitochondria.
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Vikrant
authors.initials: V
authors.lastname: Vijay
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Moland
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: James C
authors.initials: JC
authors.lastname: Fuscoe
authors.affiliation: Department of Mathematics, Korea University, Sejong, Republic of Korea.
authors.forename: Taewon
authors.initials: T
authors.lastname: Lee
authors.affiliation: Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, The National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20850-9734, United States.
authors.forename: Eugene H
authors.initials: EH
authors.lastname: Herman
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: G Ronald
authors.initials: GR
authors.lastname: Jenkins
authors.affiliation: Office of Scientific Coordination, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Sherry M
authors.initials: SM
authors.lastname: Lewis
authors.affiliation: UltraPath Imaging, 2228 Page Road, Durham, NC 27703, United States.
authors.forename: Connie A
authors.initials: CA
authors.lastname: Cummings
authors.affiliation: Biomarkers and Alternative Models Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Biomarkers and Alternative Models Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Biomarkers and Alternative Models Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Yu
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States. Electronic address: varsha.desai@fda.hhs.gov.
authors.forename: Varsha G
authors.initials: VG
authors.lastname: Desai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D002316:Cardiotonic Agents / Q000494:pharmacology*; D064730:Dexrazoxane / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D004734:Energy Metabolism / Q000235:genetics; D015870:Gene Expression; D063990:Gene Ontology; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020107:Troponin T / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D002316:Cardiotonic Agents; D020107:Troponin T; D064730:Dexrazoxane; D004317:Doxorubicin
keywords: Biomarkers; Cardiotoxicity; Dexrazoxane; Doxorubicin; Mitochondria