Honokiol, an activator of Sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice
| Autor: | Willard W. Sharp, Sadhana Samant, Abhinav Kanwal, Jack L. Arbiser, Vinodkumar B. Pillai, Mahesh P. Gupta, Yong Hu Fang |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Gerontology cardiac toxicity SIRT3 medicine.medical_treatment Mitochondrion Pharmacology doxorubicin Lignans Mitochondria Heart 03 medical and health sciences Mice Cell Line Tumor Sirtuin 3 Pathology Section medicine polycyclic compounds Animals Doxorubicin Myocytes Cardiac Cells Cultured Pressure overload Chemotherapy Cardiotoxicity biology business.industry Biphenyl Compounds Research Paper: Pathology 3. Good health Rats Up-Regulation Cardiac hypertrophy Disease Models Animal 030104 developmental biology Oncology mitochondrial fusion Sirtuin biology.protein cancer therapy business Cardiomyopathies Reactive Oxygen Species medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Vinodkumar B. Pillai 1 , Abhinav Kanwal 1 , Yong Hu Fang 2 , Willard W. Sharp 2 , Sadhana Samant 1 , Jack Arbiser 3 and Mahesh P. Gupta 1 1 Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA 2 Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA 3 Department of Dermatology, Atlanta Veterans Administration Health Center, Emory University School of Medicine, Atlanta, GA, USA Correspondence to: Mahesh P. Gupta, email: // Keywords : doxorubicin, cardiac toxicity, SIRT3, Cardiac hypertrophy, cancer therapy, Pathology Section Received : September 14, 2016 Accepted : February 27, 2017 Published : March 11, 2017 Abstract Doxorubicin is the chemotherapeutic drug of choice for a wide variety of cancers, and cardiotoxicity is one of the major side effects of doxorubicin treatment. One of the main cellular targets of doxorubicin in the heart is mitochondria. Mitochondrial sirtuin, SIRT3 has been shown to protect against doxorubicin-induced cardiotoxicity. We have recently identified honokiol (HKL) as an activator of SIRT3, which protects the heart from developing pressure overload hypertrophy. Here, we show that HKL-mediated activation of SIRT3 also protects the heart from doxorubicin-induced cardiac damage without compromising the tumor killing potential of doxorubicin. Doxorubicin-induced cardiotoxicity is associated with increased ROS production and consequent fragmentation of mitochondria and cell death. HKL-mediated activation of SIRT3 prevented Doxorubicin induced ROS production, mitochondrial damage and cell death in rat neonatal cardiomyocytes. HKL also promoted mitochondrial fusion. We also show that treatment with HKL blocked doxorubicin-induced cardiac toxicity in mice. This was associated with reduced mitochondrial DNA damage and improved mitochondrial function. Furthermore, treatments of mice, bearing prostrate tumor-xenografts, with HKL and doxorubicin showed inhibition of tumor growth with significantly reduced cardiac toxicity. Our results suggest that HKL-mediated activation of SIRT3 protects the heart from doxorubicin-induced cardiotoxicity and represents a potentially novel adjunct for chemotherapy treatments. |
| Databáze: | OpenAIRE |
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