title: Sulforaphane protects the heart from doxorubicin-induced toxicity.
abstract: Cardiotoxicity is one of the major side effects encountered during cancer chemotherapy with doxorubicin (DOX) and other anthracyclines. Previous studies have shown that oxidative stress caused by DOX is one of the primary mechanisms for its toxic effects on the heart. Since the redox-sensitive transcription factor, Nrf2, plays a major role in protecting cells from the toxic metabolites generated during oxidative stress, we examined the effects of the phytochemical sulforaphane (SFN), a potent Nrf2-activating agent, on DOX-induced cardiotoxicity. These studies were carried out both in vitro and in vivo using rat H9c2 cardiomyoblast cells and wild type 129/sv mice, and involved SFN pretreatment followed by SFN administration during DOX exposure. SFN treatment protected H9c2 cells from DOX cytotoxicity and also resulted in restored cardiac function and a significant reduction in DOX-induced cardiomyopathy and mortality in mice. Specificity of SFN induction of Nrf2 and protection of H9c2 cells was demonstrated in Nrf2 knockdown experiments. Cardiac accumulation of 4-hydroxynonenal (4-HNE) protein adducts, due to lipid peroxidation following DOX-induced oxidative stress, was significantly attenuated by SFN treatment. The respiratory function of cardiac mitochondria isolated from mice exposed to DOX alone was repressed, while SFN treatment with DOX significantly elevated mitochondrial respiratory complex activities. Co-administration of SFN reversed the DOX-associated reduction in nuclear Nrf2 binding activity and restored cardiac expression of Nrf2-regulated genes at both the RNA and protein levels. Together, our results demonstrate for the first time that the Nrf2 inducer, SFN, has the potential to provide protection against DOX-mediated cardiotoxicity.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Preeti
authors.initials: P
authors.lastname: Singh
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: McElhanon
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Allen
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, AR, USA; Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Judit K
authors.initials: JK
authors.lastname: Megyesi
authors.affiliation: Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Beneš
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Central Arkansas Veterans Healthcare System, Little Rock, AR, USA. Electronic address: ssingh@uams.edu.
authors.forename: Sharda P
authors.initials: SP
authors.lastname: Singh
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D009202:Cardiomyopathies / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004317:Doxorubicin / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression; D017879:Isothiocyanates / Q000494:pharmacology*; D015227:Lipid Peroxidation; D008297:Male; D057507:Mice, 129 Strain; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013454:Sulfoxides; D019209:Troponin C / Q000097:blood
chemical_list: D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D017382:Reactive Oxygen Species; D013454:Sulfoxides; D019209:Troponin C; D004317:Doxorubicin; C505410:Casp3 protein, rat; D053148:Caspase 3; C016766:sulforaphane
keywords: Cardiac functions; Cardiotoxicity; Doxorubicin; Nrf2; Oxidative stress; Reactive oxygen species; Sulforaphane