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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.

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  • Authors+Show Affiliations

    ,

    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.

    ,

    Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

    ,

    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.

    ,

    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.

    ,

    Central Arkansas Veterans Healthcare System, Little Rock, AR, USA; Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

    ,

    Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

    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.

    Source

    Free radical biology & medicine 86: 2015 Sep pg 90-101

    MeSH

    Animals
    Antibiotics, Antineoplastic
    Cardiomyopathies
    Cardiotonic Agents
    Caspase 3
    Cell Line
    Doxorubicin
    Drug Evaluation, Preclinical
    Gene Expression
    Isothiocyanates
    Lipid Peroxidation
    Male
    Mice, 129 Strain
    Mitochondria, Heart
    NF-E2-Related Factor 2
    Oxidative Stress
    Rats
    Reactive Oxygen Species
    Troponin C

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    26025579

    Citation

    Singh, Preeti, et al. "Sulforaphane Protects the Heart From Doxorubicin-induced Toxicity." Free Radical Biology & Medicine, vol. 86, 2015, pp. 90-101.
    Singh P, Sharma R, McElhanon K, et al. Sulforaphane protects the heart from doxorubicin-induced toxicity. Free Radic Biol Med. 2015;86:90-101.
    Singh, P., Sharma, R., McElhanon, K., Allen, C. D., Megyesi, J. K., Beneš, H., & Singh, S. P. (2015). Sulforaphane protects the heart from doxorubicin-induced toxicity. Free Radical Biology & Medicine, 86, pp. 90-101. doi:10.1016/j.freeradbiomed.2015.05.028.
    Singh P, et al. Sulforaphane Protects the Heart From Doxorubicin-induced Toxicity. Free Radic Biol Med. 2015;86:90-101. PubMed PMID: 26025579.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Sulforaphane protects the heart from doxorubicin-induced toxicity. AU - Singh,Preeti, AU - Sharma,Rajendra, AU - McElhanon,Kevin, AU - Allen,Charles D, AU - Megyesi,Judit K, AU - Beneš,Helen, AU - Singh,Sharda P, Y1 - 2015/05/27/ PY - 2014/12/31/received PY - 2015/05/04/revised PY - 2015/05/19/accepted PY - 2015/5/31/entrez PY - 2015/5/31/pubmed PY - 2016/6/4/medline KW - Cardiac functions KW - Cardiotoxicity KW - Doxorubicin KW - Nrf2 KW - Oxidative stress KW - Reactive oxygen species KW - Sulforaphane SP - 90 EP - 101 JF - Free radical biology & medicine JO - Free Radic. Biol. Med. VL - 86 N2 - 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. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/26025579/Sulforaphane_protects_the_heart_from_doxorubicin_induced_toxicity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(15)00239-7 DB - PRIME DP - Unbound Medicine ER -