Sulforaphane protects the heart from doxorubicin-induced toxicity |
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| Affiliation: | 1. Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea;2. Korea Bioactive Natural Material Bank, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea;1. The Second People''s Hospital of China Three Gorges University, Yichang 443002, China;2. Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical College, China Three Gorges University, Yichang 443002, China;3. Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic diseases(Hubei University for Nationalities), Enshi 445000, China;4. Women''s Cancer Research Center of UPMC Hillman Cancer Center, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA;5. Yichang Center for Disease Control and Prevention, Yichang 443002, China;1. Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad-500 007, India;2. Animal House, CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad-500 007, India;3. National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad-500 007, India;1. Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Innsbruck Medical University, Innsbruck A-6020, Austria;2. Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR 00936-5067, USA |
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| 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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| Keywords: | Sulforaphane Doxorubicin Nrf2 Oxidative stress Cardiotoxicity Cardiac functions Reactive oxygen species |
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