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Mitochondrial Targeting of Doxorubicin Eliminates Nuclear Effects Associated with Cardiotoxicity
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    Mitochondrial Targeting of Doxorubicin Eliminates Nuclear Effects Associated with Cardiotoxicity
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    Department of Chemistry, Faculty of Arts and Science, University of Toronto, Toronto, Ontario M5S 3H6, Canada
    Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada
    § §Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada
    Princess Margaret Cancer Center, University Health Network, Toronto, Ontario M5G 2M9, Canada
    Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada
    Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy
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    ACS Chemical Biology

    Cite this: ACS Chem. Biol. 2015, 10, 9, 2007–2015
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    https://doi.org/10.1021/acschembio.5b00268
    Published June 3, 2015
    Copyright © 2015 American Chemical Society

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    The highly effective anticancer agent doxorubicin (Dox) is a frontline drug used to treat a number of cancers. While Dox has a high level of activity against cancer cells, its clinical use is often complicated by dose-limiting cardiotoxicity. While this side effect has been linked to the drug’s direct activity in the mitochondria of cardiac cells, recent studies have shown that these result primarily from downstream effects of nuclear DNA damage. Our lab has developed a mitochondrially targeted derivative of Dox that enables the selective study of toxicity generated by the presence of Dox in the mitochondria of human cells. We demonstrate that mitochondria-targeted doxorubicin (mtDox) lacks any direct nuclear effects in H9c2 rat cardiomyocytes, and that these cells are able to undergo mitochondrial biogenesis. This recovery response compensates for the mitotoxic effects of Dox and prevents cell death in cardiomyocytes. Furthermore, cardiac toxicity was only observed in Dox but not mtDox treated mice. This study supports the hypothesis that mitochondrial damage is not the main source of the cardiotoxic effects of Dox.

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    Cite this: ACS Chem. Biol. 2015, 10, 9, 2007–2015
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acschembio.5b00268
    Published June 3, 2015
    Copyright © 2015 American Chemical Society

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